Heteroaromatic NMDA receptor modulators and uses thereof

ABSTRACT

Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated modulate the NMDA receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/060,056, filed Jun. 7, 2018, which is a 35 U.S.C. § 371 nationalstage filing of International Application No. PCT/US2016/065852, filedDec. 9, 2016, which claims priority to U.S. Provisional PatentApplication No. 62/265,182, filed Dec. 9, 2015, the contents of each ofwhich are hereby incorporated by reference in their entirety.

BACKGROUND

Diseases of the nervous system are collectively the leading cause ofhuman disability, as measured by the global burden of disease. Eventhose major diseases of the nervous system for which treatments havebeen approved by health authorities, including psychiatric diseases suchas Schizophrenia, neurological diseases such as Alzheimer's Disease, andneurodevelopmental disorders, such as Attention Deficit andHyperactivity Disorder, are poorly managed because approved treatmentshave limited efficacy and serious side effects, leaving a significantburden of unmet medical need. In addition, there are many major and rarenervous system disorders for which no treatments are approved, such asthe neurodevelopmental disorders of the Autism Spectrum, and manyintellectual disability disorders, and which are therefore associatedwith profound unmet medical need.

The N-methyl-D-aspartate-(NMDA) subtype of ligand-gated ion channelreceptors are a diverse family of glutamate receptors widely accepted tomediate synaptic transmission, key mechanisms of synaptic plasticity,and dynamic neuronal network connectivity required for normal nervoussystem development and function.

The NMDA receptor is composed of four protein subunits, two GluN1subunits and two GluN2 subunits. The GluN1 subunit is derived from asingle gene (GRIN1), is ubiquitously expressed throughout the nervoussystem, and is common to all NMDA receptors. Four different GluN2subunits, GluN2A-D, are derived from separate genes (GRIN2A-D) that aredifferentially expressed in different regions of the nervous system andby distinct populations of neurons within a particular region. A GluN3subunit has also been identified, but its function is less wellunderstood. Furthermore, individual neurons may express more than oneGluN2 subunit and individual NMDA receptors expressed by such neuronsmay contain two of the same GluN2 subunits (for example, 2GluN2Bsubunits) or two different subunits (one GluN2A and one GluN2B subunit).In addition, all NMDA receptor subunits are expressed as diverse mRNAsplice variants. Thus, native nervous system NMDA receptors are highlydiverse in their composition.

The study of the molecular basis of NMDA receptor function continues tobe an area of importance. As glutamate is the major excitatoryneurotransmitter, dysfunction of glutamate neurotransmission and NMDAreceptor-dependent mechanisms of synaptic transmission, plasticity, andneuronal network connectivity are broadly implicated in diseases of thenervous system. Accordingly, compounds that are capable of modulatingNMDA receptors may be useful for the treatment of nervous systemdisorders and diseases, for example, schizophrenia, Alzheimer's disease,attention deficit and hyperactivity disorder, and autism.

SUMMARY

The present disclosure provides, for example, compounds which aremodulators of NMDA receptors (e.g., positive allosteric modulators ofNMDA receptors) and their use as medicinal agents, processes for theirpreparation, and pharmaceutical compositions containing them as anactive ingredient. The disclosure provides for the use of disclosedcompounds as medicaments and/or in the manufacture of medicaments forthe modulation of NMDA receptors in warm-blooded animals such as humans.In particular this disclosure relates to compounds useful for thetreatment of psychiatric, neurologicial and/or neurodevelopmentaldisorders and/or diseases of the nervous system, for example,schizophrenia, Alzheimer's disease, attention deficit and hyperactivity,autism, and other nervous system-associated conditions. Also providedare pharmaceutical compositions comprising at least one disclosedcompound and a pharmaceutically acceptable carrier.

In an embodiment, provided herein are compounds represented by FormulaI:

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof, where A, B, L¹, Q, R¹, R², T, U¹, U², V, W, X, Y, and y are asdefined herein.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Before further description of the presentinvention, certain terms employed in the specification, examples andappended claims are collected here. These definitions should be read inlight of the remainder of the disclosure and as understood by a personof skill in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by a person of ordinary skill in the art.

Definitions

“Treating” includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder and the like.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon. Exemplary alkyl groups include, but are notlimited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbonatoms, referred to herein as C₁₋₆alkyl, C₁₋₄alkyl, and C₁₋₃ alkyl,respectively. Exemplary alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond.Exemplary alkenyl groups include, but are not limited to, a straight orbranched group of 2-6 or 3-4 carbon atoms, referred to herein asC₂₋₆alkenyl, and C₃₋₄alkenyl, respectively. Exemplary alkenyl groupsinclude, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkylgroup attached to oxygen (alkyl-O—). Exemplary alkoxy groups include,but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms,referred to herein as C₁₋₆alkoxy, and C₂₋₆alkoxy, respectively.Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy,isopropoxy, etc.

The term “alkylcarbonyl” as used herein refers to a straight or branchedalkyl group attached to a carbonyl group (alkyl-C(O)—). Exemplaryalkylcarbonyl groups include, but are not limited to, alkylcarbonylgroups of 1-6 atoms, referred to herein as C₁₋₆alkylcarbonyl groups.Exemplary alkylcarbonyl groups include, but are not limited to, acetyl,propanoyl, isopropanoyl, butanoyl, etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond.Exemplary alkynyl groups include, but are not limited to, straight orbranched groups of 2-6, or 3-6 carbon atoms, referred to herein asC₂₋₆alkynyl, and C₃₋₆alkynyl, respectively. Exemplary alkynyl groupsinclude, but are not limited to, ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, etc.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “cyano” as used herein refers to the radical —CN.

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers toa saturated or partially unsaturated hydrocarbon group of, for example,3-6, or 4-6 carbons, referred to herein as C₃₋₆cycloalkyl orC₄₋₆cycloalkyl, respectively. Exemplary cycloalkyl groups include, butare not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutylor cyclopropyl.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to oxygen (cycloalkyl-O—). Exemplary cycloalkoxy groupsinclude, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms,referred to herein as C₃₋₆cycloalkoxy groups. Exemplary cycloalkoxygroups include, but are not limited to, cyclopropoxy, cyclobutoxy,cyclohexyloxy, etc.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The terms “heteroaryl” or “heteroaromatic group” as used herein refersto a monocyclic aromatic 5-6 membered ring system containing one or moreheteroatoms, for example one to three heteroatoms, such as nitrogen,oxygen, and sulfur. Where possible, said heteroaryl ring may be linkedto the adjacent radical though carbon or nitrogen. Examples ofheteroaryl rings include but are not limited to furan, thiophene,pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole,triazole, pyridine or pyrimidine etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated, 4-10 membered ringstructures, including bridged or fused rings, and whose ring structuresinclude one to three heteroatoms, such as nitrogen, oxygen, and sulfur.Where possible, heterocyclyl rings may be linked to the adjacent radicalthrough carbon or nitrogen. Examples of heterocyclyl groups include, butare not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine,piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.

The term “heterocyclyloxy” as used herein refers to a heterocyclyl groupattached to oxygen (heterocyclyl-O—).

The term “heteroaryloxy” as used herein refers to a heteroaryl groupattached to oxygen (heteroaryl-O—).

The terms “hydroxy” and “hydroxyl” as used herein refers to an OHfunctionality.

The term “oxo” as used herein refers to a carbonyl functionality (e.g.,C═O).

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, and general safety and purity standards asrequired by FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The term “pharmaceutical composition” as used herein refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans. The compounds of the invention can beadministered to a mammal, such as a human, but can also be administeredto other mammals such as an animal in need of veterinary treatment,e.g., domestic animals (e.g., dogs, cats, and the like), farm animals(e.g., cows, sheep, pigs, horses, and the like) and laboratory animals(e.g., rats, mice, guinea pigs, and the like). The mammal treated in themethods of the invention is desirably a mammal in which treatment ofe.g., schizophrenia desired. “Modulation” includes antagonism (e.g.,inhibition), agonism, partial antagonism, partial agonism and allostericmodulation of agonists or antagonists.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system or animal, (e.g.mammal or human) that is being sought by the researcher, veterinarian,medical doctor or other clinician. The compounds of the invention areadministered in therapeutically effective amounts to treat a disease.Alternatively, a therapeutically effective amount of a compound is thequantity required to achieve a desired therapeutic and/or prophylacticeffect, such as an amount which results in substantially relief ofsymptoms associated with schizophrenia.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe compositions. Compounds included in the present compositions thatare basic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including, but notlimited to, malate, oxalate, chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds included in the present compositions that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts, particularly calcium, magnesium, sodium,lithium, zinc, potassium, and iron salts. Compounds included in thepresent compositions that include a basic or acidic moiety may also formpharmaceutically acceptable salts with various amino acids. Thecompounds of the disclosure may contain both acidic and basic groups;for example, one amino and one carboxylic acid group. In such a case,the compound can exist as an acid addition salt, a zwitterion, or a basesalt.

The compounds of the disclosure may be chiral or exist as stereoisomers.The term “stereoisomers” when used herein consist of all enantiomers ordiastereomers. These compounds may be designated by the symbols “(+),”“(−),” “R” or “S,” depending on the configuration of substituents aroundthe stereogenic carbon atom, but the skilled artisan will recognize thata structure may denote a stereogenic center implicitly. The presentinvention encompasses various stereoisomers of these compounds andmixtures thereof. Mixtures of enantiomers or diastereomers may bedesignated “(±)” in nomenclature, but the skilled artisan will recognizethat a structure may denote a stereogenic center implicitly.

The compounds of the disclosure may contain one or more double bondsand, therefore, exist as geometric isomers resulting from thearrangement of substituents around a carbon-carbon double bond. Thesymbol

denotes a bond that may be a single, double or triple bond as describedherein. Substituents around a carbon-carbon double bond are designatedas being in the “Z” or “E” configuration wherein the terms “Z” and “E”are used in accordance with IUPAC standards. Unless otherwise specified,structures depicting double bonds encompass both the “E” and “Z”isomers. Substituents around a carbon-carbon double bond alternativelycan be referred to as “cis” or “trans,” where “cis” representssubstituents on the same side of the double bond and “trans” representssubstituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclicring and therefore, exist as geometric isomers resulting from thearrangement of substituents around the ring. The arrangement ofsubstituents around a carbocyclic or heterocyclic ring are designated asbeing in the “Z” or “E” configuration wherein the terms “Z” and “E” areused in accordance with IUPAC standards. Unless otherwise specified,structures depicting carbocyclic or heterocyclic rings encompass both“Z” and “E” isomers. Substituents around a carbocyclic or heterocyclicrings may also be referred to as “cis” or “trans”, where the term “cis”represents substituents on the same side of the plane of the ring andthe term “trans” represents substituents on opposite sides of the planeof the ring. Mixtures of compounds wherein the substituents are disposedon both the same and opposite sides of plane of the ring are designated“cis/trans.”

Individual enantiomers and diasteriomers of compounds of the presentinvention can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns or (4)kinetic resolution using stereoselective chemical or enzymatic reagents.Racemic mixtures can also be resolved into their component enantiomersby well known methods, such as chiral-phase liquid chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations, and may involve the use ofchiral auxiliaries. For examples, see Carreira and Kvaerno, Classics inStereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in solvated as well asunsolvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. In one embodiment, thecompound is amorphous. In one embodiment, the compound is a singlepolymorph. In another embodiment, the compound is a mixture ofpolymorphs. In another embodiment, the compound is in a crystallineform.

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

For example, a compound of the invention may have one or more H atomreplaced with deuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the examples herein by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

The term “prodrug” refers to compounds that are transformed in vivo toyield a disclosed compound or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (such as by esterase, amidase, phosphatase, oxidativeand or reductive metabolism) in various locations (such as in theintestinal lumen or upon transit of the intestine, blood or liver).Prodrugs are well known in the art (for example, see Rautio,Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). Forexample, if a compound of the invention or a pharmaceutically acceptablesalt, hydrate or solvate of the compound contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁₋₈)alkyl, (C₂₋₁₂)alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethylhaving from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁₋₂)alkylamino(C₂₋₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁₋₂)alkyl, N,N-di(C₁₋₂)alkylcarbamoyl-(C₁₋₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as (C₁₋₆)alkylcarbonyloxymethyl,1-((C₁₋₆)alkylcarbonyloxy)ethyl,1-methyl-1-((C₁₋₆)alkylcarbonyloxy)ethyl (C₁₋₆)alkoxycarbonyloxymethyl,N—(C₁₋₆)alkoxycarbonylaminomethyl, succinoyl, (C₁₋₆)alkylcarbonyl,α-amino(C₁₋₄)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl,or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where eachα-aminoalkylcarbonyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

If a compound of the invention incorporates an amine functional group, aprodrug can be formed, for example, by creation of an amide orcarbamate, an N-alkylcarbonyloxyalkyl derivative, an(oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.In addition, a secondary amine can be metabolically cleaved to generatea bioactive primary amine, or a tertiary amine can metabolically cleavedto generate a bioactive primary or secondary amine. For examples, seeSimplicio, et al., Molecules 2008, 13, 519 and references therein.

I. Heteroaromatic Compounds

In certain embodiments, the present disclosure provides compounds ofFormula

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof, wherein:

-   -   rings A and B are a fused [5,6] or [6,6] heteroaromatic system;    -   Q is N or CR⁶;    -   T is N or CR⁶; and    -   y is 0 or 1 wherein    -   when y is 1, U¹ and U² are C; W and V are each independently        selected from CR⁶; one of Y and X is CR³ and one of Y and X is        CR⁶; and    -   when y is 0:    -   X is CR³ or NR³³;    -   W is selected from the group consisting of CR⁶, N or S;    -   V is selected from the group consisting of N, NR⁷, CR⁶, S and O;    -   U¹ and U² may each be C or N; wherein when one of U¹ and U² is N        the other is C; and    -   when Q is CR⁶, T is N, W is CR⁶ and X is CR³; V is not S;    -   L¹ is a bond or C₁₋₄ alkylene optionally interrupted by O, and        optionally substituted on a carbon not bound to the ring        nitrogen with one, two, or three substituents each independently        selected from halogen, OH, cyano or —NR^(a)R^(b);    -   R¹ and R² are each independently selected from the group        consisting of H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, and        C₁₋₄ alkylcarbonyl (wherein C₁₋₄ alkyl, C₃₋₆cycloalkyl,        C₁₋₄alkoxy, and C₁₋₄ alkylcarbonyl may be optionally substituted        on a carbon not bound to the nitrogen with one, two or three        substituents each independently selected from halogen, hydroxyl,        cyano, and NR^(a)R^(b)) or    -   R¹ and R², together with the nitrogen to which they are        attached, form a 3-7 membered monocyclic, bridged bicyclic,        fused bicyclic or spirocyclic heterocyclic ring which may have        an additional heteroatom selected from O, S, or N; and wherein        the 4-6 membered monocyclic, bridged bicyclic, fused bicyclic or        spirocyclic heterocyclic ring may optionally be substituted by        one, two or more substituents each selected from the group        consisting of: phenyl (optionally substituted by one, two or        three halogens), C₃-C₆cycloalkyl (optionally substituted by one,        two or three halogens), C₁₋₆alkoxy (optionally substituted by        one, two or three halogens), and C₁₋₆alkyl (optionally        substituted by one, two or three halogens), and on a carbon not        bound to the nitrogen, by one, two or more substituents each        selected from the group consisting of halogen, cyano, oxo,        NR^(a)R^(b) and hydroxyl; and wherein if said 4-6 membered        monocyclic, bridged bicyclic, fused bicyclic or spirocyclic        heterocyclic ring contains a —NH moiety that nitrogen may be        optionally substituted by a substituent selected from the group        consisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkyl-S(O)₂—,        C₁₋₆alkylcarbonyl-, and C₁₋₆alkoxycarbonyl-;    -   R³ is selected from the group consisting of phenyl, naphthyl,        heteroaryl, heterocyclyl and C₃₋₆cycloalkyl, wherein R³ is        optionally substituted with one, two or three substituents each        independently selected from C₁₋₆alkyl, halogen, OH, cyano,        C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—,        NR^(a)R^(b), C(O)OH, C₁₋₄alkoxycarbonyl, and        NR^(a)R^(b)carbonyl, wherein C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—, and        C₁₋₆alkylcarbonyl may be optionally substituted by one or more        substituents each independently selected from halogen, hydroxyl,        cyano, and NR^(a)R^(b);    -   R³³ is selected from the group consisting of phenyl, naphthyl,        heteroaryl, heterocyclyl and C₃₋₆cycloalkyl, wherein R³³ is        optionally substituted with one, two or three substituents each        independently selected from C₁₋₄ alkyl, halogen, OH, C₁₋₄alkoxy,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,        C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b), C(O)OH,        C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl, wherein C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,        C₁₋₆alkylcarbonyl may be optionally substituted by one or more        substituents each selected from halogen, hydroxyl, cyano, and        NR^(a)R^(b);    -   R⁶ is independently selected for each occurrence from the group        consisting of H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, cyano,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, heteroaryl, phenyl,        —C(═NH)— NR^(a)W, C(═N—OH)—H, C(═N—OH)—C₁₋₆alkyl, —NR^(a)R^(b),        C(O)OH, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,        NR^(a)R^(b)carbonyl-, and R^(a)R^(b)N—SO₂—, wherein phenyl and        heteroaryl are optionally substituted by one or more        substituents each selected from cyano, halogen C₁₋₄ alkyl        (optionally substituted by halogen), cyano, C₁₋₄ alkoxy,        NR^(a)R^(b), ═NR^(a), —C(═NH)— NR^(a)R^(c), and R^(a)R^(b)N—SO₂—        and where C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, and        C₃₋₆cycloalkyl are each optionally substituted by one or more        substituents each selected from the group consisting of:        hydroxyl, cyano, C₁₋₄ alkoxy, halogen, NR^(a)R^(b), ═NR^(a),        —C(═NH)— NR^(a)R^(c), cyano, and R^(a)R^(b)N—SO₂—, and    -   R⁷ is selected from the group consisting of H, C₁₋₆alkyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, heterocyclyl, heteroaryl, and        phenyl, wherein C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl may        optionally be substituted by one or more substituents each        selected from halogen, hydroxyl, C₁₋₄ alkoxy (optionally        substituted by halogen or —Si(R_(s))₀₋₃ (wherein R_(s) is H or        C₁₋₆alkyl)), cyano, —Si(R_(s))₀₋₃ (wherein R_(s) is H or        C₁₋₆alkyl), —O—Si(R_(s))₀₋₃ (wherein R_(s) is H or C₁₋₆alkyl),        and NR^(a)R^(b);    -   R^(c) is selected from the group consisting of hydrogen,        C₁₋₃alkyl, and hydroxyl;    -   R^(a) and R^(b) are independently selected, for each occurrence,        from the group consisting of: hydrogen, C₁₋₄alkylcarbonyl,        —C(O)—O—C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₁₋₃alkyl; wherein        C₁₋₃alkyl and C₃₋₆cycloalkyl may optionally be substituted on a        carbon not bound to the nitrogen by one or more substituents        selected from: fluorine, cyano, oxo and hydroxyl; or    -   R^(a) and R^(b), together with the nitrogen to which they are        attached, form a 4-6 membered heterocyclic ring which may have        an additional heteroatom selected from O, S, or N; and wherein        the 4-6 membered heterocyclic ring may optionally be substituted        on a carbon not bound to the nitrogen by one or more        substituents selected from the group consisting of: fluorine,        methyl, cyano, oxo and hydroxyl.

In some embodiments, the fused [5,6] or [6,6] heteroaromatic system maybe selected from the group consisting of:

where R³, R⁶ and R⁷ are defined above.

In certain embodiments, for example, the rings A and B may be a fused[5,6] heteroaromatic system. For example, fused [5,6] heteroaromaticsystem may be selected from the group consisting of:

For example, the fused [5,6] heteroaromatic system may be

where R³, R⁶ and R⁷ are defined above.

In some embodiments of Formula I, L¹ may be —CH₂—. In other oradditional embodiments, R¹ and R² of Formula I, together with thenitrogen to which they are attached, may form a 4-6 membered monocyclic,bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ringoptionally be substituted on a carbon by one, two or more substituentseach selected from the group consisting of: halogen, cyano, oxo,hydroxyl and C₁₋₆alkyl (optionally substituted by one, two or threehalogens).

In certain embodiments, R³ may be selected from the group consisting ofphenyl or heteroaryl, wherein R³ is optionally substituted with one, twoor three substituents each independently selected from C₁₋₄ alkyl,halogen, OH, C₁₋₄alkoxy, C₁₋₆alkenyl, C₁₋₆alkynyl, C₃₋₆ cycloalkyl,C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b), C(O)OH,C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl, wherein C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—, andC₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b).

For example, R³ may be phenyl, thiophenyl, pyrimidinyl, pyrazinyl orpyridinyl, each optionally substituted by one or two substituents eachindependently selected from halogen and C₁₋₃alkyl (optionallysubstituted by one, two or three halogens), e.g., R³ may be phenyl,optionally substituted by one or two substituents each independentlyselected from Cl, F, Br, and CF₃.

In some embodiments, R⁶ of a disclosed formula may independently foreach occurrence may be selected from H, halogen, cyano, C₁₋₄ alkyl(optionally substituted by one or two substituents each selected fromthe group consisting of —NR^(a)R^(b), C₁₋₄ alkoxy, halogen, cyano,hydroxyl, C(O)H, and ═NR^(a)), C(O)OH, C(O)H, —C(═NH)—NR^(a)R^(c),phenyl (optionally substituted by one or two substituents each selectedfrom the group consisting of NR^(a)R^(b), C₁₋₄ alkoxy, halogen, cyano,hydroxyl, C(O)H, and ═NR^(a)), pyridinyl and pyrimidinyl.

In other embodiments, a disclosed compound may be represented by:

wherein

-   -   U¹ and U² may each be C or N; wherein when one of U¹ and U² is N        the other is C (for example, U¹ may N and U² may be C, or U¹ may        be C and U² may be N);    -   T is N or CR⁶;    -   R⁶⁶ and R⁶⁷ are each independently selected from the group        consisting of halogen, C₁₋₄ alkyl (optionally substituted by        one, two, three substituents selected from halogen, hydroxyl,        cyano and NR^(a)R^(b); and    -   V is selected from the group consisting of N, NR⁷, CR⁶⁶ and S,        for example, V may be NR⁷ or V may be N, and L¹, R¹, R², R³, R⁶,        and R⁷ are defined above.

In certain embodiments, a disclosed compound may be represented by:

wherein V is NR⁷ or S, and L¹, R¹, R², R³, R⁶⁶, and R⁶ are definedabove. For example, provided herein are compounds represented by:

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof, wherein:

-   -   R¹ and R² are each independently selected from the group        consisting of H, C₁₋₄ alkyl, C₁₋₄alkoxy, and C₁₋₄ alkylcarbonyl        or    -   R¹ and R², together with the nitrogen to which they are        attached, form a 3-7 membered monocyclic, bridged bicyclic,        fused bicyclic or spirocyclic heterocyclic ring which may have        an additional heteroatom selected from O, S, or N; and wherein        the 4-6 membered monocyclic, bridged bicyclic, fused bicyclic or        spirocyclic heterocyclic ring may optionally be substituted by        one, two or more substituents each selected from the group        consisting of: phenyl (optionally substituted by one, two or        three halogens), C₃-C₆cycloalkyl (optionally substituted by one,        two or three halogens), C₁₋₆alkoxy (optionally substituted by        one, two or three halogens), and C₁₋₆ alkyl (optionally        substituted by one, two or three halogens), and on a carbon not        bound to the nitrogen, by one, two or more substituents each        selected from the group consisting of halogen, cyano, oxo,        NR^(a)R^(b) and hydroxyl; and wherein if said 4-6 membered        monocyclic, bridged bicyclic, fused bicyclic or spirocyclic        heterocyclic ring contains a —NH moiety that nitrogen may be        optionally substituted by a substituent selected from the group        consisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkyl-S(O)₂—,        C₁₋₆alkylcarbonyl-, and C₁₋₆alkoxycarbonyl-;    -   R³ is selected from the group consisting of phenyl, naphthyl,        heteroaryl, heterocyclyl and C₃₋₆cycloalkyl, wherein R³ is        optionally substituted with one, two or three substituents each        independently selected from C₁₋₆alkyl, halogen, OH, cyano,        C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—,        NR^(a)R^(b), C(O)OH, C₁₋₄alkoxy carbonyl, and        NR^(a)R^(b)carbonyl, wherein C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—, and        C₁₋₆alkylcarbonyl may be optionally substituted by one or more        substituents each independently selected from halogen, hydroxyl,        cyano, and NR^(a)R^(b);    -   R⁶ is independently selected for each occurrence from the group        consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, cyano,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, heteroaryl, phenyl,        —C(═NH)—NR^(a)R′, C(═N—OH)—H, C(═N—OH)—C₁₋₆alkyl, —NR^(a)R^(b),        C(O)OH, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,        NR^(a)R^(b)carbonyl-, and R^(a)R^(b)N—SO₂—, wherein phenyl and        heteroaryl are optionally substituted by one or more        substituents each selected from cyano, halogen C₁₋₄ alkyl        (optionally substituted by halogen), cyano, C₁₋₄alkoxy,        NR^(a)R^(b), ═NR^(a), —C(═NH)— NR^(a)R^(b), and R^(a)R^(b)N—SO₂)        and where C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, and        C₃₋₆cycloalkyl are each optionally substituted by one or more        substituents each selected from the group consisting of:        hydroxyl, cyano, C₁₋₄ alkoxy, halogen, NR^(a)R^(b), ═NR^(a),        —C(═NH)— NR^(a)R^(c), cyano, and R^(a)R^(b)N—SO₂—,    -   R⁶⁶ and R⁶⁷ are each independently selected from the group        consisting of halogen, C₁₋₄ alkyl (optionally substituted by        one, two, three substituents selected from halogen, hydroxyl,        cyano and NR^(a)R^(b)); and    -   R⁷ is selected from the group consisting of H, C₁₋₆alkyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, heterocyclyl, heteroaryl, and        phenyl, wherein C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl may        optionally be substituted by one or more substituents each        selected from halogen, hydroxyl, C₁₋₄ alkoxy (optionally        substituted by halogen or —Si(R_(s))₀₋₃ (wherein R_(s) is H or        C₁₋₆alkyl)), cyano, —Si(R_(s))₀₋₃ (wherein R_(s) is H or        C₁₋₆alkyl), —O—Si(R_(s))₀₋₃ (wherein R_(s) is H or C₁₋₆alkyl),        and NR^(a)R^(b);    -   R^(c) is selected from the group consisting of hydrogen,        C₁₋₃alkyl, and hydroxyl;    -   R^(a) and R^(b) are independently selected, for each occurrence,        from the group consisting of: hydrogen, hydroxyl, and C₁₋₃        alkyl; wherein C₁₋₃ alkyl may optionally be substituted by one        or more substituents selected from: fluorine, cyano, oxo and        hydroxyl; or    -   R^(a) and R^(b), together with the nitrogen to which they are        attached, form a 4-6 membered heterocyclic ring which may have        an additional heteroatom selected from O, S, or N.

In some embodiments, R¹ and R², together with the nitrogen to which theyare attached, may form a 4-6 membered monocyclic, bridged bicyclic,fused bicyclic or spirocyclic heterocyclic ring optionally substitutedon a carbon not adjacent to the nitrogen by one, two or moresubstituents each selected from the group consisting of: halogen, cyano,oxo, hydroxyl and C₁₋₆alkyl (optionally substituted by one, two or threehalogens).

In certain embodiments, R³ may be selected from the group consisting ofphenyl or heteroaryl, wherein R³ is optionally substituted with one, twoor three substituents each independently selected from C₁₋₄ alkyl,halogen, OH, C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl,C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b),C(O)OH, C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl, wherein C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—, andC₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b).

For example, R³ may be phenyl, thiophenyl, pyrimidinyl, pyrazinyl orpyridinyl, each optionally substituted by one or two substituents eachindependently selected from halogen and C₁₋₃alkyl (optionallysubstituted by one, two or three halogens).

In an embodiment, R⁷ may be selected from the group consisting of H,C₁₋₆alkyl, C₃₋₆cycloalkyl, heteroaryl, and phenyl, wherein C₁₋₆alkyl isoptionally substituted by one or more substituents each selected fromhalogen, hydroxyl, C₁₋₄ alkoxy (optionally substituted by halogen or—Si(R_(s))₀₋₃ (wherein R_(s) is H or C₁₋₆alkyl), cyano, andNR^(a)R^(b)).

Procedures for making compounds disclosed herein are provided below. Inthe reactions described below, it may be necessary to protect reactivefunctional groups (such as hydroxyl, amino, thio or carboxyl groups) toavoid their unwanted participation in the reactions. The incorporationof such groups, and the methods required to introduce and remove themare known to those skilled in the art (for example, see Greene, Wuts,Protective Groups in Organic Synthesis. 2nd Ed. (1999)). Thedeprotection step may be the final step in the synthesis such that theremoval of protecting groups affords compounds of Formula I. Startingmaterials used in the following schemes can be purchased or prepared bymethods described in the chemical literature, or by adaptations thereof,using methods known by those skilled in the art. The order in which thesteps are performed can vary depending on the groups introduced and thereagents used, but would be apparent to those skilled in the art.

Compounds of any of Formula I, II, III, IV, as depicted above, or any ofthe intermediates described below, can be further derivatised by usingone or more standard synthetic methods known to those skilled in theart. Such methods can involve substitution, oxidation or reductionreactions. These methods can also be used to obtain or modify compoundsof Formula I or any preceding intermediates by modifying, introducing orremoving appropriate functional groups. Particular substitutionapproaches include alkylation, arylation, heteroarylation, acylation,thioacylation, halogenation, sulfonylation, nitration, formylation,hydrolysis and coupling procedures. These procedures can be used tointroduce a functional group onto the parent molecule (such as thenitration or sulfonylation of aromatic rings) or to couple two moleculestogether (for example to couple an amine to a carboxylic acid to affordan amide; or to form a carbon-carbon bond between two heterocycles). Forexample, alcohol or phenol groups can be converted to ether groups bycoupling a phenol with an alcohol in a solvent (such as tetrahydrofuran)in the presence of a phosphine (such as triphenylphosphine) and adehydrating agent (such as diethyl, diisopropyl or dimethylazodicarboxylate). Alternatively, ether groups can be prepared bydeprotonation of an alcohol, using a suitable base (such as sodiumhydride) followed by the addition of an alkylating agent (such as analkyl halide or an alkyl sulfonate).

In another example, a primary or secondary amine can be alkylated usinga reductive alkylation procedure. For example, the amine can be treatedwith an aldehyde and a borohydride (such as sodiumtriacetoxyborohydride, or sodium cyanoborohydride in a solvent (such asa halogenated hydrocarbon, for example dichloromethane, or an alcohol,for example ethanol) and, where necessary, in the presence of an acid(such as acetic acid).

In another example, hydroxy groups (including phenolic OH groups) can beconverted into leaving groups, such as halogen atoms or sulfonyloxygroups (such as alkylsulfonyloxy, for exampletrifluoromethanesulfonyloxy, or aryl sulphonyloxy, for examplep-toluenesulfonyloxy) using conditions known to those skilled in theart. For example, an aliphatic alcohol can be reacted with thionylchloride in a halogenated hydrocarbon (such as dichloromethane) toafford the corresponding alkyl chloride. A base (such as triethylamine)can also be used in the reaction.

In another example, ester groups can be converted to the correspondingcarboxylic acid group by acid- or base-catalysed hydrolysis depending onthe nature of the ester group. Acid catalysed hydrolysis can be achievedby treatment with an organic or inorganic acid (such as trifluoroaceticacid in an aqueous solvent, or a mineral acid such as hydrochloric acidin a solvent such as dioxane). Base catalysed hydrolysis can be achievedby treatment with an alkali metal hydroxide (such as lithium hydroxidein an aqueous alcohol, for example methanol).

In another example, aromatic halogen substituents in the compounds maybe subjected to halogen-metal exchange by treatment with a base (such asa lithium base, for example n-butyl or t-butyllithium) optionally at alow temperature (such as −78° C.) in a solvent (such as tetrahydrofuran)and the mixture may then be quenched with an electrophile to introduce adesired substituent. Thus, for example, a formyl group can be introducedby using dimethylformamide as the electrophile. Aromatic halogensubstituents can also be subjected to palladium catalysed reactions tointroduce groups such as carboxylic acids, esters, cyano or aminosubstituents.

In another example, an aryl, or heteroaryl ring substituted with anappropriate leaving group (such as a halogen or sulfonyl ester, forexample a triflate) can undergo a palladium catalysed coupling reactionwith a wide variety of substrates to form a carbon-carbon bond. Forexample, a Heck reaction can be used to couple such a ring system to analkene (which may, or may not, be further substituted) by treatment withan organopalladium complex (such astetrakis(triphenylphosphine)palladium(0), palladium (II) acetate orpalladium (II) chloride) in the presence of a ligand (such as aphosphine, for example triphenylphosphine) in the presence of a base(such as potassium carbonate or a tertiary amine, for example,triethylamine), in an appropriate solvent (such as tetrahydrofuran orDMF), under appropriate conditions (such as heating to, for example,50-120° C.). In another example, a Sonogashira reaction can be used tocouple such a ring system to an alkyne (which may, or may not be furthersubstituted) by treatment with a palladium complex (such astetrakis(triphenylphosphine)palladium(0)) and a halide salt of copper(I) (such as copper (I) iodide), in the presence of a base (such as apotassium carbonate or a tertiary amine, for example, triethylamine), inan appropriate solvent (such as tetrahydrofuran or dimethylformamide),under appropriate conditions (such as heating to, for example, 50-120°C.). In another example, a Stille reaction can be used to couple such aring system to an alkene, by treatment with an organotin compound (suchas an alkynyltin or alkenyltin reagent, for example analkenyltributylstannane) in the presence of a palladium complex (such astetrakis(triphenylphosphine)palladium(0)), with, or without the presenceof a salt (such as a copper (1) halide), in an appropriate solvent (suchas dioxane or dimethylformamide), under appropriate conditions (such asheating to, for example, 50-120° C.).

Particular oxidation approaches include dehydrogenations andaromatisation, decarboxylation and the addition of oxygen to certainfunctional groups. For example, aldehyde groups can be prepared byoxidation of the corresponding alcohol using conditions well known tothose skilled in the art. For example, an alcohol can be treated with anoxidising agent (such as Dess-Martin periodinane) in a solvent (such asa halogenated hydrocarbon, for example dichloromethane). Alternativeoxidising conditions can be used, such as treatment with oxalyl chlorideand an activating amount of dimethylsulfoxide and subsequent quenchingby the addition of an amine (such as triethylamine). Such a reaction canbe carried out in an appropriate solvent (such as a halogenatedhydrocarbon, for example dichloromethane) and under appropriateconditions (such as cooling below room temperature, for example to −78°C. followed by warming to room temperature). In another example, sulfuratoms can be oxidised to the corresponding sulfoxide or sulfone using anoxidising agent (such as a peroxy acid, for example3-chloroperoxybenzoic acid) in an inert solvent (such as a halogenatedhydrocarbon, for example dichloromethane) at around ambient temperature.

Particular reduction approaches include the removal of oxygen atoms fromparticular functional groups or saturation (or partial saturation) ofunsaturated compounds including aromatic or heteroaromatic rings. Forexample, primary alcohols can be generated from the corresponding esteror aldehyde by reduction, using a metal hydride (such as lithiumaluminium hydride or sodium borohydride in a solvent such as methanol).Alternatively, CH₂OH groups can be generated from the correspondingcarboxylic acid by reduction, using a metal hydride (such as lithiumaluminium hydride in a solvent such as tetrahydrofuran). In anotherexample, a nitro group may be reduced to an amine by catalytichydrogenation in the presence of a metal catalyst (such as palladium ona solid support such as carbon) in a solvent (such as an ether, forexample tetrahydrofuran, or an alcohol, such as methanol), or bychemical reduction using a metal (such as zinc, tin or iron) in thepresence of an acid (such as acetic acid or hydrochloric acid). In afurther example an amine can be obtained by reduction of a nitrile, forexample by catalytic hydrogenation in the presence of a metal catalyst(such as palladium on a solid support such as carbon), or Raney nickelin a solvent (such as tetrahydrofuran) and under suitable conditions(such as cooling to below room temperature, for example to −78° C., orheating, for example to reflux).

Salts of compounds of Formula I (e.g., Formula II, III, IV) can beprepared by the reaction of a compound of Formula I with an appropriateacid or base in a suitable solvent, or mixture of solvents (such as anether, for example, diethyl ether, or an alcohol, for example ethanol,or an aqueous solvent) using conventional procedures. Salts of compoundof Formula I can be exchanged for other salts by treatment usingconventional ion-exchange chromatography procedures.

Where it is desired to obtain a particular enantiomer of a compound ofFormula I, this may be produced from a corresponding mixture ofenantiomers by employing any suitable conventional procedure forresolving enantiomers. For example, diastereomeric derivatives (such assalts) can be produced by reaction of a mixture of enantiomers of acompound of Formula I (such a racemate) and an appropriate chiralcompound (such as a chiral base). The diastereomers can then beseparated by any conventional means such as crystallisation, and thedesired enantiomer recovered (such as by treatment with an acid in theinstance where the diastereomer is a salt). Alternatively, a racemicmixture of esters can be resolved by kinetic hydrolysis using a varietyof biocatalysts (for example, see Patel Steroselective Biocatalysts,Marcel Decker; New York 2000).

In another resolution process a racemate of compounds of Formula I canbe separated using chiral High Performance Liquid Chromatography.Alternatively, a particular enantiomer can be obtained by using anappropriate chiral intermediate in one of the processes described above.Chromatography, recrystallisation and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular geometric isomer of the invention.

II. Methods

Another aspect of the disclosure provides methods of modulating theactivity of the NMDA receptor. Such methods may for example, compriseexposing said receptor to a compound described herein. In someembodiments, the compound utilized by one or more of the foregoingmethods is one of the generic, subgeneric, or specific compoundsdescribed herein, such as a compound of Formula I. The ability ofcompounds described herein to modulate the NMDA receptor can beevaluated by procedures known in the art and/or described herein.

In certain embodiments, the present disclosure provides a method oftreating and or ameliorating a disease and/or disorder of the nervoussystem in a patient in need thereof by administering an effective amountof a disclosed compound. Exemplary diseases and disorders of the nervoussystem include psychiatric diseases, neurological diseases, andneurodevelopmental disorders, further described below.

In one embodiment, an exemplary psychiatric disease is schizophrenia.Schizophrenia is a debilitating mental disorder encompassing threesymptom domains: positive (psychosis, hallucination, delusions),negative (withdrawal), and cognitive (global reduction in cognitiveability). Positive symptoms of Schizophrenia typically emerge early inadulthood and are treated with antipsychotic medications. However,cognitive deficits are severe, emerge in the adolescent prodromal stage,are resistant to antipsychotic therapy, and are the leading cause oflifetime disability as measured by impaired global function (inabilityto live independently, unemployment, etc). NMDA receptor hypofunction isthe leading hypothesis for the cause of schizophrenia. This hypothesisis supported by substantial clinical evidence including clinicalpharmacology, electrophysiology, imaging, cognition, computationalneuroscience, neuroanatomical studies, and genetics. In particular,several lines of evidence implicate hypofunction of GluN2B-containingNMDA receptors in schizophrenia.

The present disclosure provides herein a method of treatingschizophrenia, including positive, negative, and cognitive symptoms, ina patient in need thereof, comprising administering an effective amountof a disclosed compound. For example, provided herein are methods ofameliorating positive, negative, and cognitive symptoms of a patient notadequately treated by approved antipsychotic medications, for examplethe treatment of cognitive impairments in schizophrenia, byadministering an effective amount of a disclosed compound to such apatient.

Also provided herein are methods to improve cognitive and globalfunction, and/or substantially preventing the onset of schizophrenia inpeople at risk of developing schizophrenia, by administering aneffective amount of a disclosed compound to such a patient.

Contemplated herein are methods of treating and/or amelioratingcognitive and emotional deficits and other symptoms associated withexemplary psychiatric disorders including major depressive disorder, andincluding but not limited to those suffering from bipolar disorder,obsessive-compulsive disorder, dysphoric disorder, dysthymic disorder,psychotic depression, post-traumatic stress disorder, and other anxietydisorders. For example, provided herein are methods of treatingattention deficit disorder, ADHD (attention deficit hyperactivitydisorder), schizophrenia, anxiety, amelioration of opiate, nicotineand/or ethanol addiction (e.g., method of treating such addiction orameliorating the side effects of withdrawing from such addiction),spinal cord injury, diabetic retinopathy, traumatic brain injury, and/orpost-traumatic stress syndrome in a patient in need thereof, thatincludes administering a disclosed compound.

In other embodiments, provided herein is a method of treating and/orameliorating cognitive and emotional deficits and other symptomsresulting from neurological diseases, including but not limited to apatient suffering from Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis,and seizure disorders comprising administering to the patient aneffective amount of a disclosed compound.

The present disclosure contemplates a method of treating and/orameliorating dysfunction caused by neurodevelopmental disorders, e.g.,abnormal brain development, including but not limited to Rett Syndrome,Attention Deficit and Hyperactivity Disorder, autism and autism spectrumdisorders such as Phelan-McDermid Syndrome, and other forms ofintellectual disability such as Fragile X syndrome, tuberous sclerosis,Smith-Lemli-Opitz Syndrome, and Down's syndrome. A method is alsoprovided to treat patients suffering from abnormal brain functionresulting from infections of the central nervous system, exposure totoxic agents or other xenobiotics or naturally occurring toxins, and/orautoimmune disorders including, but not limited to anti-NMDA receptorencephalitis comprising administering an effective amount of a disclosedcompound.

In particular, in certain embodiments, the disclosure provides a methodof treating, preventing, and/or preventing the development of the abovemedical indications comprising administering to a subject in needthereof a therapeutically effective amount of a compound describedherein, such as a compound of Formula I, II, III or IV.

In certain embodiments, the compound utilized by one or more of theforegoing methods is one of the generic, subgeneric, or specificcompounds described herein, such as a compound of Formula I II, III orIV.

Disclosed compounds may be administered to patients in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.It will be appreciated that the dose required for use in any particularapplication will vary from patient to patient, not only with theparticular compound or composition selected, but also with the route ofadministration, the nature of the condition being treated, the age andcondition of the patient, concurrent medication or special diets thenbeing followed by the patient, and other factors which those skilled inthe art will recognize, with the appropriate dosage ultimately being atthe discretion of the attendant physician. For treating clinicalconditions and diseases noted above, a compound of this invention may beadministered orally, subcutaneously, topically, parenterally, byinhalation spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. Parenteral administration may include subcutaneousinjections, intravenous or intramuscular injections or infusiontechniques.

Treatment can be continued for as long or as short a period as desired.The compositions may be administered on a regimen of, for example, oneto four or more times per day. A suitable treatment period can be, forexample, at least about one week, at least about two weeks, at leastabout one month, at least about six months, at least about 1 year, orindefinitely. A treatment regimen can include a corrective phase, duringwhich dose sufficient to maintain cognitive and/or emotional function isadministered, and can be followed by a maintenance phase, during which,e.g., a lower dose sufficient to prevent a deficit in cognitive and/oremotional function is administered. A suitable maintenance dose islikely to be found in the lower parts of the dose ranges providedherein, but corrective and maintenance doses can readily be establishedfor individual subjects by those of skill in the art without undueexperimentation, based on the disclosure herein.

III. Pharmaceutical Compositions and Kits

Another aspect of the invention provides pharmaceutical compositionscomprising compounds as disclosed herein formulated together with apharmaceutically acceptable carrier. In particular, the presentdisclosure provides pharmaceutical compositions comprising compounds asdisclosed herein formulated together with one or more pharmaceuticallyacceptable carriers. These formulations include those suitable for oral,rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular,intradermal, or intravenous) rectal, vaginal, or aerosol administration,although the most suitable form of administration in any given case willdepend on the degree and severity of the condition being treated and onthe nature of the particular compound being used. For example, disclosedcompositions may be formulated as a unit dose, and/or may be formulatedfor oral or subcutaneous administration.

Exemplary pharmaceutical compositions of this invention may be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains one or more of the compound ofthe invention, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The active objectcompound is included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or conditionof the disease.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical carrier, e.g.,conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.In the case of capsules, tablets and pills, the compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, cyclodextrins and mixtures thereof.

Suspensions, in addition to the subject composition, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the body cavity and release theactive agent.

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. The active component may be mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to asubject composition, excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Compositions and compounds of the present invention may alternatively beadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. A non-aqueous (e.g., fluorocarbon propellant) suspension couldbe used. Sonic nebulizers may be used because they minimize exposing theagent to shear, which may result in degradation of the compoundscontained in the subject compositions. Ordinarily, an aqueous aerosol ismade by formulating an aqueous solution or suspension of a subjectcomposition together with conventional pharmaceutically acceptablecarriers and stabilizers. The carriers and stabilizers vary with therequirements of the particular subject composition, but typicallyinclude non-ionic surfactants (Tweens, Pluronics, or polyethyleneglycol), innocuous proteins like serum albumin, sorbitan esters, oleicacid, lecithin, amino acids such as glycine, buffers, salts, sugars orsugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions of the present disclosure suitable forparenteral administration comprise a subject composition in combinationwith one or more pharmaceutically-acceptable sterile isotonic aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, or sterilepowders which may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate and cyclodextrins. Proper fluidity may be maintained,for example, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants

In another aspect, the invention provides enteral pharmaceuticalformulations including a disclosed compound and an enteric material; anda pharmaceutically acceptable carrier or excipient thereof. Entericmaterials refer to polymers that are substantially insoluble in theacidic environment of the stomach, and that are predominantly soluble inintestinal fluids at specific pHs. The small intestine is the part ofthe gastrointestinal tract (gut) between the stomach and the largeintestine, and includes the duodenum, jejunum, and ileum. The pH of theduodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH ofthe distal ileum is about 7.5. Accordingly, enteric materials are notsoluble, for example, until a pH of about 5.0, of about 5.2, of about5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary entericmaterials include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP),hydroxypropyl methylcellulose acetate succinate (HPMCAS), celluloseacetate trimellitate, hydroxypropyl methylcellulose succinate, celluloseacetate succinate, cellulose acetate hexahydrophthalate, cellulosepropionate phthalate, cellulose acetate maleate, cellulose acetatebutyrate, cellulose acetate propionate, copolymer of methylmethacrylicacid and methyl methacrylate, copolymer of methyl acrylate,methylmethacrylate and methacrylic acid, copolymer of methylvinyl etherand maleic anhydride (Gantrez ES series), ethylmethylacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylatecopolymer, natural resins such as zein, shellac and copal collophorium,and several commercially available enteric dispersion systems (e.g.,Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, KollicoatEMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of eachof the above materials is either known or is readily determinable invitro. The foregoing is a list of possible materials, but one of skillin the art with the benefit of the disclosure would recognize that it isnot comprehensive and that there are other enteric materials that wouldmeet the objectives of the present invention.

Pharmaceutical compositions of the present disclosure may also beadministered by the use of monoclonal antibodies as individual carriersto which the disclosed compounds are coupled. The disclosed compoundscan also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, Disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Advantageously, the invention also provides kits for use by, e.g., aconsumer in need of a disclosed NMDA modulator. Such kits include asuitable dosage form such as those described above and instructionsdescribing the method of using such dosage form to mediate, reduce orprevent inflammation. The instructions would direct the consumer ormedical personnel to administer the dosage form according toadministration modes known to those skilled in the art. Such kits couldadvantageously be packaged and sold in single or multiple kit units. Anexample of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a first compound can consistof one tablet or capsule while a daily dose of the second compound canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

EXAMPLES

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials.

At least some of the compounds identified as “Intermediates” herein arecontemplated as compounds of the invention.

¹H NMR spectral chemical shifts are expressed in ppm relative totetramethylsilane. The following abbreviations have been used: br=broadsignal, s=singlet, d=doublet, dd=double doublet, ddd=double doubledoublet, dt=double triplet, t=triplet, td=triple doublet, q=quartet,m=multiplet.

A. Preparation of Thienopyridones Example 1: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of3-bromo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of 3-bromothieno[3,2-c]pyridin-4(5H)-one (1 g,4.34 mmol) in dry acetone (10 mL), potassium carbonate (1.8 g, 13.02mmol) and 2-chloro-1-(pyrrolidin-1-yl)ethanone (0.96 g, 6.52 mmol) wasadded at room temperature and the reaction mixture was heated at refluxfor 6 h. The reaction mixture was concentrated, the residue was dilutedwith water and extracted with ethyl acetate (3×10 mL). The combinedorganic layer was dried over sodium sulfate, filtered and concentratedto get crude compound which was washed with pentane (2×20 mL) to affordthe title compound3-bromo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(1.4 g, 94.59% yield) as off white solid. Calculated (M+H): 340.99;Found (M+H): 340.9.

Step 2:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-bromo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.15 g, 0.43 mmol) and 4-chloro-3-(trifluoromethyl)phenyl)boronic acid(0.145 g, 0.65 mmol) in dioxane:water (5 mL, 4:1) was added sodiumcarbonate (0.139 g, 1.31 mmol). The suspension was purged with argon for15 minutes and bis(triphenylphosphine)palladium(II) dichloride (0.03 g,0.04 mmol) was added. The reaction mixture was heated at 100° C. for 2h. The reaction mixture was cooled to room temperature, diluted withwater and extracted with ethyl acetate (2×25 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto get crude compound which was purified by silica gel columnchromatography using 2% methanol in dichloromethane to get the titlecompound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.12 g, 62.17% yield) as yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.85 (s, 1H), 7.69 (d, J=4.4 Hz, 3H),7.48 (d, J=7.2 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 4.72 (s, 2H), 3.46 (t,J=6.6 Hz, 2H), 3.24 (s, 2H), 1.91 (t, J=6.6 Hz, 2H), 1.75 (t, J=6.6 Hz,2H). Calculated (M+H): 441.06; Found (M+H): 441. HPLC purity: 98.36%

TABLE 1 The following compounds were prepared by the method describedabove: Example Number Structure IUPAC Name Analytical Data 2

3-(4-chloro-3- fluorophenyl)-5-(2- oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.60 (s, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.48-7.44 (m, 2H), 7.28(d, J = 8 Hz 1H), 6.93 (d, J = 6.8 Hz, 1H), 4.72 (s, 2H), 3.47 (t, J =6.8 Hz, 2H), 3.27 (t, J = 9.6 Hz, 2H), 1.93-1.87 (m, 2H), 1.78-1.72 (m,2H). Calculated (M + H): 391.06; Found (M + H): 391.0. HPLC purity:99.39% 3

3-(3-chloro-4- fluorophenyl)-5-(2- oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.60 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.47-7.45 (d, J = 7.6 Hz,1H), 7.41-7.34 (m, 2H), 6.92 (d, J = 7.2 Hz, 1H), 4.72 (s, 2H), 3.47 (t,J = 6.8 Hz, 2H), 3.24 (s, 2H), 1.93- 1.87 (m, 2H), 1.78-1.72 (m, 2H).Calculated (M + H): 391.8; Found (M + H): 391.0. HPLC purity: 99.87%

Example 4: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of ethyl2-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetate

To a stirred solution of 3-bromothieno[3,2-c]pyridin-4(5H)-one (1 g,4.34 mmol) in dry acetone (20 mL) was added potassium carbonate (1.8 g,13.04 mmol) followed by ethyl 2-bromoacetate (0.96 mL g, 8.69 mmol) atroom temperature and the reaction mixture was heated at reflux for 12 h.The reaction mixture was concentrated, the residue was diluted withwater (30 mL) and extracted with ethyl acetate (3×30 mL). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to get crude compound which was washed with pentane (2×20mL) to get the title compound ethyl2-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetate (1.8 g, crude) asoff white solid. Calculated (M+H): 315.96; Found (M+H): 316.0.

Step-2:

Preparation of 2-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetic acid

To a stirred solution of ethyl2-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetate (1.8 g, 5.69 mmol)in tetrahydrofuran:water mixture (10 mL, 1:1) was added lithiumhydroxide monohydrate (1.1 g, 28.48 mmol) and the reaction mixture wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated, the residue was diluted with water and the pH was adjustedto −2 using 1.5N hydrochloric acid. The obtained solid was filtered anddried under vacuum to get the title compound2-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetic acid (1.1 g, 65.01%yield) as off white solid. Calculated (M+H): 287.93; Found (M+H): 287.9.

Step-3:

Preparation3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of2-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetic acid (0.4 g, 1.38mmol) in dichloromethane (10 mL) was added triethylamine (0.38 mL, 2.76mmol) at room temperature and stirred for 10 minutes.3-fluoropyrrolidine hydrochloride (0.2 g, 1.65 mmol) was added and thereaction mixture was cooled to 0° C. Then 1-propanephosphonic anhydridesolution (T₃P) (1.3 mL, 2.07 mmol, 50% in ethyl acetate) was added andthe reaction mixture was stirred at room temperature for 12 h. Thesolution was diluted with water and extracted with dichloromethane (3×30mL). The combined organic layer was dried over anhydrous sodium sulfate,filtered and concentrated to get the crude compound which was washedwith pentane (3×10 mL) to get title compound3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.36 g, 73.46% yield) as brown solid. Calculated (M+H): 358.98; Found(M+H): 359.

Step-4:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.12 g, 0.33 mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronic acid(0.112 g, 0.50 mmol) in dioxane:water mixture (5 mL, 4:1) was addedsodium carbonate (0.106 g, 1.02 mmol) and the reaction mixture waspurged with argon for 15 minutes. Thenbis(triphenylphosphine)palladium(II) dichloride (0.023 g, 0.033 mmol)was added and reaction mixture was heated at 100° C. for 2 h. Thereaction mixture was cooled to room temperature, diluted with water andextracted with ethyl acetate (4×25 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated to getthe crude compound which was purified by silica gel columnchromatography using 2% methanol in dichloromethane to get the titlecompound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one (0.031 g, 20.3% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.86 (s, 1H), 7.73-7.67 (m,3H), 7.49 (d, J=7.6 Hz, 1H), 6.97 (d, J=6.8 Hz, 1H), 5.48-5.23 (m, 1H),4.86-4.69 (m, 2H), 3.86-3.26 (m, 4H), 2.30-1.91 (m, 2H). Calculated(M+H): 459.05; Found (M+H): 459. HPLC purity: 98.85%

TABLE 2 The following compounds were prepared by the method describedabove: Example Number Structure IUPAC Name Analytical Data  5

3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-(3,3-difluoroazetidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.87 (s, 1H), 7.73-7.68 (m, 3H), 7.50(d, J = 6.8 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 4.70-4.66 (m, 4H), 4.30(t, J = 11.2 Hz, 2H). Calculated (M + H): 463.02; Found (M + H): 463.HPLC purity: 98.90%  6

3-(4-chloro-3- fluorophenyl)-5-(2- (3,3-difluoroazetidin- 1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.63 (s, 1H), 7.54 (t, J =8.4 Hz, 1H), 7.5- 7.44 (m, 2H), 7.29(d, J = 8.4 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.72-4.66 (m, 4H), 4.31(t, J = 12 Hz, 2H). Calculated (M + H): 413.03: Found (M + H): 413.0.HPLC purity: 98.29%  7

3-(4-chloro-3- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.61 (s, 1H), 7.55-7.43 (m, 3H), 7.29 (d, J = 8 Hz 1H), 6.94 (d,J = 6.8 Hz, 1H), 5.48-5.23 (m, 1H), 4.86-4.73 (m, 2H), 3.86-3.73 (m,2H), 3.69-3.27 (m, 2H), 2.3-2.06 (m, 2H). Calculated (M + H): 409.05;Found (M + H): 409.0. HPLC purity: 99.72%  8

3-(3-Chloro-4- fluorophenyl)-5-[2- (3,3-difluoro- azetidin1-yl)-2-oxo-ethyl]-5H-thieno[3,2- c]pyridin-4-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.62-7.59 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.42-7.35 (m, 2H),6.95 (d, J = 7.6 Hz, 1H), 4.72- 4.67 (m, 4H), 4.31 (t, J = 11.6 Hz, 2H).Calculated (M + H): 413.03; Found (M + H): 413.0. HPLC purity: 99.37%  9

3-(3-Chloro-4-fluoro- phenyl)-5-[2-(3- fluoro-pyrrolidin-1-yl)-2-oxo-ethyl]-5H- thieno[3,2-c]pyridin- 4-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.62-7.59 (m, 1H), 7.58 (s, 1H), 7.49-7.47 (m, 1H),7.43-7.34 (m, 2H), 6.93 (d, J = 7.2 Hz, 1H), 5.48-5.23 (m, 1H),4.86-4.69 (m, 2H), 3.86-3.23 (m, 4H), 2.30-1.89 (m, 2H). Calculated (M +H): 409.05; Found (M + H): 409.3. HPLC purity: 99.87% 10

3-(3,4- dichlorophenyl)-5-(2- (3-fluoropyrrolidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.66 (s, 1H), 7.62 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48 (d, J= 7.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H),5.48-5.23 (m, 1H), 4.86-4.69 (m, 2H), 3.83-3.27 (m, 4H), 2.24-1.94 (m,2H). Calculated (M + H): 425.02; Found (M + H): 425.0. HPLC purity:99.79% 11

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.78 (d, J = 6.0 Hz, 2H), 7.65 (s, 1H),7.5- 7.45 (m, 2H), 6.95 (d, J = 6.8 Hz, 1H), 5.47-5.23 (m, 1H),4.86-4.69 (m, 2H), 3.86-3.64 (m, 2H), 3.60-3.27 (m, 2H), 2.3-1.91 (m,2H). Calculated (M + H): 443.08; Found (M + H): 443.0. HPLC purity:99.94%. 12

3-(5,6- dichloropyridin-3-yl)- 5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 8.43 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H),7.51 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 6.8 Hz, 1H), 5.48-5.23 (m, 1H),4.88-4.71 (m, 2H), 3.86-3.26 (m, 4H), 2.30-1.91 (m, 2H). Calculated (M +H): 426.02; Found (M + H): 426.0. HPLC purity: 99.81%. 13

3-(3-chloro-4- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.81 (d, J = 8 Hz, 1H), 7.73 (d, J =9.6 Hz, 2H), 7.60 (d, J = 10 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6.96 (d,J = 7.2 Hz, 1H), 5.48- 5.23 (m, 1H), 4.87-4.70 (m, 2H), 3.85-3.38 (m,4H), 2.30-2.02 (m, 2H); Calculated (M + H): 459.05, Found (M + H):459.0, HPLC purity: 98.67% 14

3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-((3S,4R)-3,4-difluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.86 (s, 1H), 7.73-7.67 (m, 3H), 7.47(d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 5.44-5.21 (m, 2H),4.82-4.73 (m, 2H), 4.03-3.96 (m, 1H), 3.94-3.59 (m, 2H), 3.5-3.22 (m,1H). Calculated (M + H): 477.04; Found (M + H): 477.0. HPLC purity:99.16%. 15

(S)-3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.86 (s, 1H), 7.72-7.69 (m, 3H), 7.49(d, J = 6.4 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 5.47-5.22 (m, 1H),4.86-4.69 (m, 2H), 3.86-3.27 (m, 4H), 2.3-1.91 (m, 2H). Calculated (M +H): 459.05; Found (M + H): 459.0. HPLC purity: 99.82%. 16

3-(3,4- dichlorophenyl)-5-(2- ((3S,4R)-3,4- difluoropyrrolidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.66 (d, J = 2.0 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H),7.46 (d, J = 2.0 Hz, 1H), 7.39 (dd, J₁ = 8.0 Hz & J₂ = 8.4 Hz, 1H), 6.94(d, J = 7.2 Hz, 1H), 5.45-5.21 (m, 2H), 4.82-4.72 (m, 2H), 4.03-3.96 (m,1H), 3.77-3.61 (m, 2H), 3.5-3.27 (m, 1H). Calculated (M + H): 443.01;Found (M + H): 443.0. HPLC purity: 98.44%. 17

(R)-3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.86 (s, 1H), 7.73-7.67 (m, 3H), 7.49(d, J = 6.8 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 5.48-5.23 (m, 1H),4.87-4.69 (m, 2H), 3.86-3.22 (m, 4H), 2.30-1.88 (m, 2H). Calculated (M +H): 459.05; Found (M + H): 459.0. HPLC purity: 99.69%. 18

3-(4-chloro-3- fluorophenyl)-5-(2-(3- fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 7.63 (s, 1H), 7.57-7.45 (m, 3H), 7.30 (d, J = 8.4 Hz, 1H), 6.95(d, J = 7.2 Hz, 1H), 4.61 (s, 2H), 4.38-4.25 (m, 2H), 3.96 (d, J = 19.2Hz, 2H), 1.58 (d, J = 22 Hz, 3H). Calculated (M + H): 409.05; Found (M +1): 409.0. HPLC purity 99.82% 19

3-(5-chloro-6- fluoropyridin-3-yl)-5- (2-(3-fluoro-3-methylazetidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO- d₆) δ (ppm); 8.25-8.24 (m, 2H), 7.76 (s, 1H), 7.51 (d, J= 7.2 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 4.63 (s, 2H), 4.39-4.26 (m,2H), 3.96 (d, J = 20.4 Hz, 2H), 1.58 (d, J = 22 Hz, 3H). Calculated (M +H): 410.05; Found (M + 1): 410.0. HPLC purity 99.59% 20

3-(3,4- difluorophenyl)-5-(2- (3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H-NMR (400 MHz, DMSO- d₆) δ(ppm): 7.58 (s, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.45-7.36 (m, 1H), 7.27(brs, 1H), 6.95 (d, J = 6.8 Hz, 1H), 4.61 (s, 2H), 4.38-4.25 (m, 2H),3.98 (d, J = 19.2 Hz, 2H), 1.60 (d, J = 30 Hz, 3H), Calculated (M + H):393.08, Found (M + H): 393.1, HPLC purity: 99.65% 21

3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoro-3-methylazetidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H-NMR(400 MHz, DMSO- d₆) δ (ppm): 7.88 (s, 1H), 7.74-7.69 (m, 3H), 7.51 (d, J= 7.2 Hz, IH), 6.98 (d, J = 7.6 Hz, 1H), 4.60 (s, 2H), 4.38-4.25 (m,2H), 4.01-3.92 (m, 2H), 1.60 (d, J = 22.4 Hz, 3H). Calculated (M + H):459.0, Found (M + H): 459.0, HPLC purity: 99.92% 22

3-(4-chloro-3- methylphenyl)-5-(2- (3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.49 (s, 1H), 4.47 (d, J = 7.2 Hz, 1H), 7.39-7.35 (m, 2H), 7.24(d, J = 8.0 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 4.59 (s, 2H), 4.37-4.24(m, 2H), 3.95 (d, J = 19.2 Hz, 2H), 2.33 (s, 3H), 1.57 (d, J = 22.4 Hz,3H). Calculated (M + H): 405.08; Found (M + H): 405.0. HPLC Purity:99.92% 23

5-(2-(3-fluoro-3- methylazetidin-1-yl)- 2-oxoethyl)-3-(4-fluoro-3-methyl- phenyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO- d₆) δ (ppm): 7.47-7.45 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H),7.24-7.23 (m, 1H), 7.08 (t, J = 9.6 Hz, 1H), 6.92 (d, J = 6.8 Hz, 1H),4.59 (s, 2H), 4.37-4.24 (m, 2H), 3.95 (d, J = 10.8 Hz, 2H), 2.23 (s,3H), 1.57 (d, J = 22.4 Hz, 3H). Calculated (M + H): 389.11; Found (M +H): 389.0. HPLC Purity: 99.62%

Example 24: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(3-(3-fluoropyrrolidin-1-yl)-3-oxopropyl)thieno[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of ethyl3-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)propanoate

To a stirred solution of 3-bromothieno[3,2-c]pyridin-4(5H)-one (1 g,4.34 mmol) in dry acetone (25 mL) at room temperature was addedpotassium carbonate (1.8 g, 13.03 mmol) followed by ethyl3-bromopropanoate (1.1 mL, 8.69 mmol) and the reaction mixture washeated at 55° C. for 48 h. The reaction mixture was filtered and thefiltrate was concentrated under vacuum. The crude product was purifiedby silica gel column chromatography using 1% methanol in dichloromethaneto afford the title compound ethyl3-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)propanoate (0.14 g, 9%yield) as yellow liquid.

Calculated (M+H): 329.97; Found (M+H): 330.0.

Step-2:

Preparation of3-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)propanoicacid

To a solution of ethyl3-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)propanoate (0.14 g, 0.42mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (0.14 g, 0.63mmol) in 1,4-dioxane:water mixture (10 mL, 4:1), potassium carbonate(0.176 g, 1.27 mmol) was added. Then the reaction purged with argon for15 minutes. Then PdCl₂(PPh₃)₂ (0.029 g, 0.04 mmol) was added and thereaction mixture was stirred at 100° C. for 18 h. Then reaction mixturewas diluted with ethyl acetate (100 mL) and washed with water (2×30 mL).The aqueous layer was separated and acidified with 1.5N hydrochloricacid at 0° C. The precipitated solid was filtered and dried undersuction to afford the title compound3-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)propanoicacid (0.06 g, 35% yield) as black solid. Calculated (M+H): 402.01; Found(M+H): 402.0.

Step-3:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(3-(3-fluoropyrrolidin-1-yl)-3-oxopropyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)propanoicacid (0.06 g, 0.14 mmol) and 3-fluoropyrrolidine hydrochloride (0.028 g,0.22 mmol) in dichloromethane (12 mL) was added triethylamine (0.14 mL,1.04 mmol) at room temperature. The reaction mixture was cooled to 0°C., 1-propanephosphonic anhydride solution (T₃P) (0.14 mL, 0.22 mmol,50% in ethyl acetate) was added drop-wise and the reaction mixture wasstirred at room temperature for 18 h. The reaction mixture was dilutedwith water (20 mL) and extracted with dichloromethane (2×60 mL). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The crude product was purified by silicagel column chromatography using 1% methanol in dichloromethane to affordthe title compound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(3-(3-fluoropyrrolidin-1-yl)-3-oxopropyl)thieno[3,2-c]pyridin-4(5H)-one(0.03 g, 42% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.90 (s, 1H), 7.76 (d, J=8 Hz, 1H), 7.70-7.64 (m, 3H), 6.93 (d, J=7.2Hz, 1H), 5.23-5.42 (m, 1H), 4.11 (brs, 2H), 3.55-3.52 (m, 2H), 3.42-3.32(m, 1H), 3.30-3.26 (m, 1H), 2.69-2.64 (m, 2H), 2.30-2.20 (m, 2H),Calculated (M+H): 473.06, Found (M+H): 473.0, HPLC purity: 99.36%.

TABLE 3 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 25

3-(6-chloro-5- (trifluoro- methyl)pyridin-3- yl)-5-(2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.72 (d, J = 2.0 Hz, 1H), 8.36 (d, J =2.0 Hz, 1H), 7.87 (s, 1H), 7.52 (dd, J = 1.6 Hz, 6.8 Hz, 1H), 6.99 (d, J= 7.2 Hz, 1H), 5.48-5.23 (m, 1H), 4.89-4.71 (m, 2H), 3.87-3.22 (m, 4H),2.3-1.88 (m, 2H). Calculated (M + H): 460.04; Found (M + H): 460.0. HPLCpurity: 99.2% 26

(S)-3-(4-fluoro-3- (trifluoro- methyl)phenyl)-5- (2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 7.77 (d, J = 6.0 Hz, 2H), 7.49-7.45 (s,1H), 6.94 (d, J = 7.6 Hz, 2H), 6.95 (d, J = 7.2 Hz, 1H), 5.48-5.23 (m,1H), 4.88-4.69 (m, 2H), 3.86-3.35 (m, 4H), 2.3-1.91 (m, 2H). Calculated(M + H): 443.08; Found (M + H): 443.1; HPLC purity: 99.13% 27

(R)-3-(4-fluoro-3- (trifluoro- methyl)phenyl)-5- (2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 7.77 (d, J = 6.0 Hz, 2H), 7.65 (s, 1H),7.5-7.45 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 5.48-5.23 (m, 1H), 4.87-4.69(m, 2H), 3.86-3.22 (m, 4H), 2.3-1.88 (m, 2H). Calculated (M + H):443.08; Found (M + H): 443.1; HPLC purity: 99.67% 28

5-(2-((3S,4R)-3,4- difluoropyrrolidin-1- yl)-2-oxoethyl)-3-(4- fluoro-3-(trifluoromethyl) phenyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 7.77 (d, J = 6.0 Hz, 2H), 7.66 (s, 1H), 7.5-7.46(m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 5.44-5.21 (m, 2H), 4.82-4.73 (m, 2H),4.03-3.95 (m, 1H), 3.77-3.6 (m, 2H), 3.49-3.27 (m, 1H). Calculated (M +H): 461.07; Found (M + H): 461.1; HPLC purity: 99.82% 29

(R)-3-(3,4- dichlorophenyl)-5- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.66 (s, 1H), 7.62 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48 (d, J= 7.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 6.8 Hz, 1H),5.48-5.23 (m, 1H), 4.86-4.69 (m, 2H), 3.86- 3.27 (m, 4H), 2.23-1.91 (m,2H). Calculated (M + H): 425.02; Found (M + H): 425.0. HPLC purity:98.98% 30

(S)-3-(3,4- dichlorophenyl)-5- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.66 (d, J = 2 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H),7.48 (d, J = 7.6 Hz, 1H), 7.41-7.38 (dd, J = 2.0 Hz, 8 Hz, 1H), 6.93 (d,J = 6.8 Hz, 1H), 5.48-5.23 (m, 1H),. 4.86- 4.69 (m, 2H), 3.86-3.26 (m,4H), 2.30-1.91 (m, 2H). Calculated (M + H): 425.02; Found (M + H):425.0. HPLC purity: 97.66% 31

3-(5-chlorothiophen- 2-yl)-5-(2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.73 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.3 (d, J = 3.2 Hz, 1H),7.03 (d, J = 4.0 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 5.50-5.25 (m, 1H),4.88-4.71 (m, 2H), 3.88-3.27 (m, 4H), 2.26-1.96 (m, 2H). Calculated (M +H): 397.02; Found (M + H): 397.0. HPLC purity: 97.66% 32

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3- fluoroazetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.79-7.76 (m, 2H), 7.66 (s, 1H), 7.51-7.46 (m, 2H), 6.95 (d, J =7.2 Hz, 1H), 5.49- 5.33 (m, 1H), 4.59-4.48 (m, 3H), 4.32-4.13 (m, 2H),3.94- 3.85 (m, 1H). Calculated (M + H): 429.06; Found (M + H): 429.0;HPLC purity: 99.82%. 33

3-(3,4- dichlorophenyl)-5- (2-(3-fluoroazetidin- 1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one 1H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.66 (s, 1H), 7.62 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.48 (d, J= 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H),5.48-5.34 (m, 1H), 4.59-4.48 (m, 3H), 4.32-4.11 (m, 2H), 3.94-3.85 (m,1H). Calculated (M + H): 411.01; Found (M + H): 411.0; HPLC purity:99.21% 34

3-(4-chloro-3- (trifluoromethyl) phenyl)-5-(2-(3- fluoroazetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.86 (s, 1H), 7.73-7.68 (m, 3H), 7.49 (d, J = 7.2 Hz, 1H), 6.96(d, J = 7.6 Hz, 1H), 5.48-5.33 (m, 1H), 4.59 (s, 2H), 4.57-4.49 (m, 1H),4.32-4.14 (m, 2H), 3.94-3.88 (m, 1H). Calculated (M + H): 445.03; Found(M+H): 445.0; HPLC purity: 99.19% 35

3-(5,6- dichloropyridin-3- yl)-5-(2-(3,4- difluoropyrrolidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.43 (s, 1H), 8.19 (s, 1H), 7.79 (s, 1H), 7.49 (d, J = 7.2 Hz,1H), 6.99 (d, J = 7.2 Hz, 1H), 5.45-5.22 (m, 2H), 4.84- 4.74 (m, 2H),4.04-3.78 (m, 1H), 3.74-3.61 (m, 2H), 3.50- 3.27 (m, 1H). Calculated(M + H): 444.01, Found (M + H): 444.0. HPLC purity: 99.56% 36

3-(6-chloro-5- (trifluoromethyl) pyridin-3-yl)-5-(2- (3,4-difluoro-pyrrolidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.73 (s, 1H), 8.36 (s, 1H), 7.87 (s, 1H),7.50 (d, J = 6.8 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H), 5.45-5.22 (m, 2H),4.84- 4.74 (m, 2H), 4.04-3.96 (m, 1H), 3.78-3.61 (m, 2H), 3.60- 3.27 (m,1H). Calculated (M + H): 478.03, Found (M + H): 478.0. HPLC purity:99.62% 37

3-(5-chloro-6- fluoropyridin-3-yl)- 5-(2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.25-8.23 (m, 2H), 7.75 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 6.98(d, J = 7.6 Hz, 1H), 5.49-5.24 (m, 1H), 4.89- 4.71 (m, 2H), 3.87-3.39(m, 4H), 2.30-1.90 (m, 2H). Calculated (M + H): 410.05, Found (M + H):410.2. HPLC purity: 99.69% 38

3-(5-chloro-6- fluoropyridin-3-yl)- 5-(2-(3,4- difluoropyrrolidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400MHz) δ (ppm): 8.25-8.23 (m, 2H), 7.76 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H),6.98 (d, J = 6.8 Hz, 1H), 5.45-5.22 (m, 2H), 4.85- 4.75 (m, 2H),4.05-3.96 (m, 1H), 3.78-3.61 (m, 2H), 3.51- 3.42 (m, 1H). Calculated(M + H): 428.04, Found (M + H): 428.0. HPLC purity: 99.14% 39

3-(3-chloro-4- fluorophenyl)-5-(2- (3-fluoro-3- methylazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.62-7.59 (m, 2H), 7.48 (d, J = 6.8 Hz, 1H), 7.44- 7.35 (m, 2H),6.94 (d, J = 6.8 Hz, 1H), 4.61 (s, 2H), 4.38-4.25 (m, 2H). 3.95 (d, J =18.8 Hz, 2H), 1.57 (d, J = 21.6 Hz, 3H). Calculated (M + H): 409.05;Found (M + H): 409.0. HPLC purity: 98.35% 40

(S)-3-(3-chloro-4- fluorophenyl)-5-(2- (3-fluoropyrrolidin- 1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.62-7.58 (m, 2H), 7.48 (s, J = 7.2 Hz, 1H), 7.43- 7.35 (m, 2H),6.93 (d, J = 7.2 Hz, 1H), 5.48-5.24 (m, 1H), 4.87-4.70 (m, 2H),3.83-3.27 (m, 4H), 2.30-2.05 (m, 2H). Calculated (M + H): 409.05; Found(M + H): 409.0. HPLC purity: 98.01% 41

(R)-3-(3-chloro-4- fluorophenyl)-5-(2- (3-fluoropyrrolidin- 1-yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.62-7.58 (m, 2H), 7.48 (s, J = 7.2 Hz, 1H), 7.43- 7.35 (m, 2H),6.94 (d, J = 6.8 Hz, 1H), 5.49-5.24 (m, 1H), 4.87-4.70 (m, 2H),3.83-3.27 (m, 4H), 2.30-2.07 (m, 2H). Calculated (M + H): 409.05; Found(M + H): 409.0. HPLC purity: 98.53% 42

3-(3,4- dichlorophenyl)-5- (2-(3-fluoro-3- methylazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.67 (s, 1H), 7.64 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.49 (d, J= 6 Hz, 1H), 7.40 (d, J = 8 Hz, 1H), 6.96 (d, J = 6.8 Hz, 1H), 4.61 (s,2H), 4.38-4.25 (m, 2H), 3.95 (d, J = 19.6 Hz, 2H), 1.57 (d, J = 22 Hz,3H). Calculated (M + H): 425.02; Found (M + H): 425.0. HPLC purity:98.33% 43

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoro-3-methylazetidin-1- yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 7.80-7.78 (m, 2H), 7.67 (s, 1H),7.51-7.47 (m, 2H), 6.97 (d, J = 6.8 Hz, 1H), 4.60 (s, 2H), 4.38-4.25 (m,2H), 4.00-3.92 (m, 2H), 1.56 (d, J = 22 Hz, 3H). Calculated (M + H):443.08; Found (M + H): 443.1. HPLC purity: 99.55% 44

3-(3-chloro-4- fluorophenyl)-5-(2- (3-cyclopropyl-3-fluoroazetidin-1-yl)- 2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO- d₆) δ (ppm); 7.62-7.59 (m, 2H), 7.49 (d, J = 6.8 Hz,1H), 7.42- 7.35 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 4.60-4.58 (m, 2H),4.25-4.18 (m, 2H), 3.89-3.84 (m, 2H), 1.37 (s, 1H), 0.58 (d, J = 7.6 Hz,2H), 0.48 (s, 1H), 0.39 (s, 1H). Calculated (M + H): 435.07; Found (M +H): 435.1. HPLC purity 98.81% 45

5-(2-(3-cyclopropyl- 3-fluoroazetidin-1- yl)-2-oxoethyl)-3-(4- fluoro-3-(trifluoromethyl) phenyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 7.80-7.78 (m, 2H), 7.66 (s, 1H), 7.51-7.46 (m,2H), 6.96 (d, J = 7.2 Hz, 1H), 4.63- 4.54 (m, 2H), 4.27-4.15 (m, 2H),3.91-3.79 (m, 2H), 1.36 (s, 1H), 0.57 (d, J = 7.2 Hz, 2H), 0.47 (s, 1H),0.38 (s, 1H). Calculated (M + H): 469.09; Found (M + H): 469.1. HPLCpurity 99.54% 46

5-(2-(azetidin-1-yl)- 2-oxoethyl)-3-(3- chloro-4-fluoro-phenyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.61 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 7.2 Hz, 1H),7.40-7.36 (m, 2H), 6.93 (d, J = 7.2 Hz, 1H), 4.53 (s, 2H), 4.18 (t, J =7.6 Hz, 2H), 3.85 (t, J = 7.2 Hz, 2H), 2.25-2.21 (m, 2H). Calculated(M + H): 377.04, Found (M + H): 377.0, HPLC purity: 97.0% 47

3-(3-chloro-4- fluorophenyl)-5-(2- (3-fluoroazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.62-7.60 (m, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H),7.44-7.35 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 5.50- 5.34 (m, 1H), 4.602(s, 2H), 4.55-4.32 (m, 1H), 4.30-4.15 (m, 2H), 3.95-3.86 (m, 1H);Calculated (M + H): 395.04, Found (M + H): 395.0, HPLC purity: 98.2% 48

3-(3-chloro-4- fluorophenyl)-5-(2- (3-methylazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.61 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 6.8 Hz, 1H),7.41-7.35 (m, 2H), 6.93 (d, J = 6.8 Hz, 1H), 4.54 (s, 2H), 4.28 (t, J =8.4 Hz, 1H), 3.95 (t, J = 8.8 Hz, 1H), 3.74 (t, J = 5.6 Hz, 1H), 3.41(t, J = 6.0 Hz, 1H), 2.70-2.65 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H).Calculated (M + H): 391.06, Found (M + H): 391.1, HPLC purity: 97.84% 49

5-(2-(3-cyclopropyl- 3-fluoroazetidin-1- yl)-2-oxoethyl)-3-(3,4-dichloro- phenyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO- d₆) δ (ppm): 7.67 (d, J = 2.0 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J =8 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.40 (dd, J = 2.4 Hz, 8.4 Hz, 1H),6.95 (d, J = 7.2 Hz, 1H), 4.64-4.55 (m, 2H), 4.28- 4.16 (m, 2H),3.89-3.80 (m, 2H), 1.42-1.33 (m, 1H), 0.59- 0.39 (m, 4H). Calculated(M + H): 451.04, Found (M + H): 451.0, HPLC purity: 98.27% 50

3-(3,4- dichlorophenyl)-5- (2-(3-ethyl-3- fluoroazetidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.67-7.58 (m, 3H), 7.49 (d, J = 9.6 Hz, 1H), 7.41 (d, J = 8.4 Hz,1H), 6.95 (d, J = 7.2 Hz, 1H), 4.61 (s, 2H), 4.36-4.24 (m, 2H),4.00-3.86 (m, 2H), 1.91-1.80 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).Calculated (M + H): 438.04; Found (M + H): 438.0. HPLC purity: 98.83% 51

5-(2-(3-ethyl-3- fluoroazetidin-1-yl)- 2-oxoethyl)-3-(4- fluoro-3-(trifluoromethyl) phenyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 7.78 (s, 2H), 7.66 (s, 1H), 7.49 (t, J = 7.6 Hz,2H), 7.96 (d, J = 7.6 Hz, 1H), 4.60 (s, 2H), 4.36-4.24 (m, 2H),3.90-3.74 (m, 2H), 1.90-1.79 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H).Calculated (M + H): 457.09; Found (M + H): 457.1. HPLC purity: 99.01% 52

3-(3-chloro-4- fluorophenyl)-5-(2- (3-ethyl-3- fluoroazetidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.62-7.59 (m, 2H), 7.48 (d, J = 7.2 Hz, 1H), 7.41- 7.35 (m, 2H),6.94 (d, J = 7.2 Hz, 1H), 4.61 (s, 2H), 4.40- 4.24 (m, 2H), 4.00-3.86(m, 2H), 1.91-1.80 (m, 2H), 0.92- 0.88 (m, 3H). Calculated (M + H):423.07; Found (M + H): 423.0. HPLC purity: 99.94% 53

3-(3,4- dichlorophenyl)-5- (2-(3-fluoro-3- phenylazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 7.68 (s, 1H), 7.65 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.55-7.51(m, 3H), 7.42 (d, J = 6.4 Hz, 4H), 6.97 (d, J = 7.2 Hz, 1H), 4.82-4.68(m, 4H), 4.33 (d, J = 21.2 Hz, 2H). Calculated (M + H): 487.04; Found(M + 1): 487.0. HPLC purity 98.15% 54

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3- fluoro-3-phenyl-azetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 7.81-7.79 (m, 2H), 7.67 (s, 1H), 7.54-7.41 (m,7H), 6.98 (d, J = 7.6 Hz, 1H), 4.80- 4.69 (m, 4H), 4.33 (d, J = 21.6 Hz,2H). Calculated (M + H): 505.09; Found (M +1): 505.1. HPLC purity 99.91%55

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3- hydroxy-3-methylazetidin-1- yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 7.78 (d, J = 6.0 Hz, 2H), 7.65 (s, 1H), 7.48(s, 2H), 6.95 (d, J = 7.2 Hz, 1H), 5.66 (s, 1H), 4.57 (s, 2H), 4.04-4.00(m, 2H), 3.71-3.68 (m, 2H), 1.35 (s, 3H). Calculated (M + H): 441.08;Found (M + H): 441.1. HPLC purity: 99.91% 56

2-(3-(3-chloro-4- fluorophenyl)-4- oxothieno[3,2- c]pyridin-5(4H)-yl)-N-(2,2,2-trifluoro- ethyl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.81 (t, J = 6.4 Hz, 1H), 7.63-7.54 (m, 3H), 7.48- 7.35 (m, 2H), 6.94(d, J = 7.2 Hz, 1H), 4.65 (s, 2H), 3.94-3.85 (m, 2H). Calculated (M +H): 419.02; Found (M + H): 419.0. HPLC Purity: 98.32% 57

3-(3-chloro-4- fluorophenyl)-5-(2- (3-fluoro-3- phenylazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 7.64-7.60 (m, 2H), 7.53-7.51 (m, 3H), 7.43-7.36 (m, 5H), 6.96 (d,J = 7.2 Hz, 1H), 4.81-4.69 (m, 4H), 4.33 (d, J = 21.2 Hz, 2H).Calculated (M + H): 471.07; Found (M + 1): 471.2. HPLC purity 99.72% 58

3-(3-chloro-4- fluorophenyl)-5-(2- (3-hydroxy-3- methylazetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm); 7.61 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J = 7.6Hz, 1H), 7.41-7.35 (m, 2H), 6.93 (d, J = 7.2 Hz, 1H), 5.67 (s, 1H), 4.57(s, 2H), 4.04-3.99 (m, 2H), 3.72-3.66 (m, 2H), 1.36 (s, 3H). Calculated(M + H): 407.06; Found (M + 1): 407.0. HPLC purity 98.70% 59

3-(3,4- dichlorophenyl)-5- (2-(3- methylazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.66 (d, J = 2 Hz, 1H), 7.62 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H),7.48 (d, J = 12 Hz, 1H), 7.41-7.39 (m, 1H), 6.93 (d, J = 7.2 Hz, 1H),4.54 (t, J = 16.4 Hz, 2H), 4.28 (t, J = 8.4 Hz, 1H), 3.95 (t, J = 8.8Hz, 1H), 3.75-3.72 (m, 1H), 3.42- 3.38 (m, 1H), 2.74-2.65 (m, 1H), 1.17(d, J = 6.8 Hz, 3H). Calculated (M + H): 407.03; Found (M + H): 407.0.HPLC purity: 99.10% 60

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3- methylazetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 7.79-7.78 (m, 2H), 7.65 (s, 1H), 7.51-7.47 (m, 2H),6.95 (d, J = 6.8 Hz, 1H), 4.54 (s, 2H), 4.28 (t, J = 8.4 Hz, 1H), 3.95(t, J = 8.8 Hz, 1H), 3.74 (t, J = 6 Hz, 1H), 3.42-3.38 (m, 1H),2.70-2.65 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H). Calculated (M + H): 425.09;Found (M + H): 425.1. HPLC purity: 99.44% 61

3-(3,4- dichlorophenyl)-5- (2-(3-hydroxy-3- methylazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.66-7.58 (m, 3H), 7.48 (d, J = 7.2 Hz, 1H), 7.40 (d J = 6.4 Hz,1H), 6.94 (d, J = 7.2 Hz, 1H), 5.67 (s, 1H), 4.57 (s, 2H), 4.04-3.98 (m,2H), 3.72- 3.66 (m, 2H), 1.36 (s, 3H). Calculated (M + H): 423.03; Found(M + H): 423.0. HPLC purity: 99.64% 62

3-(3-chloro-4- fluorophenyl)-5-(2- (3-methoxy-3- methylazetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 7.62-7.58 (m, 2H), 7.48 (s, J = 6.8 Hz, 1H), 7.41-7.35 (m, 2H), 6.93 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.13 (d, J = 7.2Hz, 1H), 3.99 (d, J = 8.8 Hz, 1H), 3.77 (d, J = 9.6 Hz, 1H), 3.64 (d, J= 10.0 Hz, 1H), 3.15 (s, 3H), 1.40 (s, 3H). Calculated (M + H): 421.07;Found (M + H): 421.1. HPLC purity: 99.86% 63

3-(3,4- dichlorophenyl)-5- (2-(3-methoxy-3- methylazetidin-1- yl)-2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.67 (s, 1H), 7.63 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.49 (d, J= 6.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 4.59(s, 2H), 4.13 (d, J = 8.8 Hz, 1H), 4.99 (d, J = 8.8 Hz, 1H), 3.78 (d, J= 9.6 Hz, 1H), 3.65 (d, J = 9.6 Hz, 1H), 3.16 (s, 3H), 1.40 (s, 3H).Calculated (M + H): 437.04; Found (M + H): 437.0. HPLC Purity: 98.42% 64

3-(4-fluoro-3-(tri- fluoromethyl)phenyl)- 5-(2-(3- methoxy-3-methylazetidin-1- yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one 1H NMR(400 MHz, DMSO-d₆) δ (ppm): 7.80-7.78 (m, 2H), 7.66 (s, 1H), 7.51-7.47(m, 2H), 6.96 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.13 (d, J = 8.8 Hz,1H), 3.99 (d, J = 8.8 Hz, 1H), 3.78 (d, J = 9.6 Hz, 1H), 3.64 (d, J =10.0 Hz, 1H), 3.15 (s, 3H), 1.39 (s, 3H). Calculated (M + H): 455.1;Found (M + H): 455.1. HPLC Purity: 98.94% 65

3-(3-chloro-4- fluorophenyl)-5-(2- (6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO- d₆) δ (ppm); 7.62-7.58 (m, 2H), 7.46-7.35 (m, 3H), 6.92 (d, J =7.2 Hz, 1H), 4.72 (s, 2H), 3.88 (s, 2H), 3.68-3.57 (m, 2H), 2.71-2.53(m, 2H). Calculated (M + H): 439.04; Found (M + 1): 439.0. HPLC purity99.01% 66

3-(3,4- dichlorophenyl)-5- (2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO- d₆) δ (ppm); 7.63-7.58 (m, 3H), 7.50-7.38 (m, 2H), 6.93 (d, J =7.6 Hz, 1H), 4.72 (s, 2H), 3.88 (s, 2H), 3.68-3.57 (m, 2H), 2.68-2.51(m, 2H). Calculated (M + H): 455.01; Found (M + 1): 455.0. HPLC purity95.52% 67

3-(3-chloro-4- fluorophenyl)-5-(2- oxo-2-(2-oxa-6- azaspiro[3.3]heptan-6- yl)ethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.61-7.58 (m, 2H), 7.45-7.35 (m, 3H), 6.93 (d, J = 6.8 Hz, 1H),4.65 (d, J = 4 Hz, 4H), 4.53 (s, 2H), 4.36 (s, 2H), 4.03 (s, 2H).Calculated (M + H): 419.06; Found (M + H): 419.0. HPLC purity: 99.37% 68

3-(3,4- dichlorophenyl)-5- (2-oxo-2-(2-oxa-6- azaspiro[3.3]heptan- 6-yl)ethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.66 (s, 1H), 7.62 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.45 (d, J= 7.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H),4.66-4.63 (m, 4H), 4.53 (s, 2H), 4.36 (s, 2H), 4.03 (s, 2H). Calculated(M + H): 435.03; Found (M + H): 435.0. HPLC purity: 99.00% 69

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-oxo-2- (2-oxa-6-azaspiro[3.3]heptan- 6- yl)ethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 7.79-7.75 (m, 2H), 7.65 (s, 1H), 7.51-7.45(m, 2H), 6.94 (d, J = 6.8 Hz, 1H), 4.67- 4.63 (m, 4H), 4.53 (s, 2H),4.36 (s, 2H), 4.03 (s, 2H). Calculated (M + H): 453.08; Found (M + H):453.1. HPLC purity: 99.56% 70

5-(2-(3-cyclopropyl- 3-fluoroazetidin-1- yl)-2-oxoethyl)-3-(5,6-dichloropyridin- 3-yl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.44 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.81 (s,1H), 7.53 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 4.66-4.56 (m,2H), 4.29-4.17 (m, 2H), 3.92-3.80 (m, 2H), 1.39-1.36 (m, 1H), 0.59-0.400(m, 4H). Calculated (M + H): 452.03; Found (M + H): 452.0. HPLC purity:98.05% 71

3-(3-chloro-4- fluorophenyl)-5-(2- oxo-2-(5- azaspiro[2.3]hexan- 5-yl)ethyl)thieno[3,2- c]pyridin-4(5H)-one 1H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.62-7.58 (m, 2H), 7.50 (d, J = 6.8 Hz, 1H), 7.42- 7.36 (m, 2H),6.94 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.24 (s, 2H), 3.91 (s, 2H), 0.63(d, J = 7.2 Hz, 4H). Calculated (M + H): 403.6; Found (M + H): 403.1.HPLC purity: 95.22% 72

5-(2-(6,6-difluoro-3- azabicyclo[3.1.0] hexan-3-yl)-2- oxoethyl)-3-(4-fluoro-3- (trifluoromethyl) phenyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm); 7.87-7.77 (m, 2H), 7.65 (s, 1H),7.50-7.45 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 4.72 (s, 2H), 3.87 (s, 2H),3.67-3.59 (m, 2H), 2.68-2.48 (m, 2H). Calculated (M + H): 473.07; Found(M + 1): 473.1. HPLC purity 99.36% 73

tert-butyl (1-(2-(3- (3,4- dichlorophenyl)-4- oxothieno[3,2-c]pyridin-5(4H)- yl)acetyl)-3- methylazetidin-3- yl)carbamate ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 7.67 (s, 1H), 7.63 (s, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.4 (d, J = 6.8 Hz, 2H), 6.94 (d, J =6.8 Hz, 1H), 4.57 (s, 2H), 4.2 (d, J = 7.2 Hz, 1H) 3.98 (d, J = 8.8 Hz,1H), 3.89 (d, J = 9.6 Hz, 1H), 3.62 (d, J = 9.6 Hz, 1H), 1.39 (d, J =18.8 Hz, 3H), 1.37 (s, 9H). Calculated (M + H): 522.1, Found (M + H):522.1, HPLC purity: 94.32% 74

tert-butyl (1-(2-(3- (3-chloro-4- fluorophenyl)-4- oxothieno[3,2-c]pyridin-5(4H)- yl)acetyl)-3- methylazetidin-3- yl)carbamate ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 7.61 (d, J = 7.2 Hz, 1H), 7.59 (s, 1H), 7.48(d, J = 6.8 Hz, 1H), 7.41-7.35 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 4.57(s, 2H), 4.20 (d, J = 8.0 Hz, 1H), 3.98 (d, J = 8.4 Hz, 1H), 3.89 (d, J= 9.6 Hz, 1H), 3.62 (d, J = 9.6 Hz, 1H), 1.42 (s, 3H), 1.37 (s, 9H).Calculated (M + H): 506.12, Found (M + H): 506.1. HPLC purity: 95.02% 75

3-(5,6- dichloropyridin-3- yl)-5-(2-(3-ethyl-3- fluoroazetidin-1-yl)- 2-oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.44 (d, J = 1.6 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.81 (s, 1H),7.52 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H), 4.63 (s, 2H),4.35-4.28 (m, 2H), 3.98-3.89 (m, 2H), 1.90- 1.82 (m, 2H), 0.90 (t, J =7.2 Hz, 3H). Calculated (M + H): 440.03; Found (M + H): 440.0. HPLCPurity: 99.54% 76

3-(5,6- dichloropyridin-3- yl)-5-(2-(3-fluoro-3- methylazetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.44 (d, 1.6 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.81(s, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 4.62 (s,2H), 4.39-4.26 (m, 2H), 3.98-3.90 (m, 2H), 1.58 (d, J = 22.0 Hz, 3H).Calculated (M + H): 426.02; Found (M + H): 426.2. HPLC Purity: 98.19% 77

tert-butyl (1-(2-(3- (4-fluoro-3- (trifluoromethyl) phenyl)-4-oxothieno[3,2- c]pyridin-5(4H)- yl)acetyl)-3- methylazetidin-3-yl)carbamate ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.80-7.76 (m, 2H), 7.66(s, 1H), 7.51-7.46 (m, 2H), 7.39 (brs, 1H), 6.96 (d, J = 7.2 Hz, 1H),4.57 (s, 2H), 4.20-3.90 (m, 3H), 3.61 (d, J = 10.0 Hz, 1H), 1.41 (s,3H), 1.37 (s, 9H). Calculated (M + H): 540.15; Found (M + H): 540.0.HPLC Purity: 99.07% 78

3-(3,4- dichlorophenyl)-5- (2-oxo-2-(5- azaspiro[2.3]hexan- 5-yl)ethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.67 (d, J = 1.6 Hz, 1H), 7.63 (m, 2H), 7.50 (d, J = 7.2 Hz, 1H),7.41 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 4.59 (s,2H), 4.24 (s, 2H), 3.91 (s, 2H), 0.63 (d, J = 7.2 Hz, 4H). Calculated(M + H): 419.03; Found (M + H): 419.0. HPLC purity: 98.35% 79

tert-butyl 6-(2-(3-(3- chloro-4- fluorophenyl)-4- oxothieno[3,2-c]pyridin-5(4H)- yl)acetyl)-1,6- diazaspiro[3.3] heptane-1-carboxylate¹H NMR (400 MHz, DMSO- d₆) δ (ppm); 7.62 (d, J = 7.2 Hz, 1H), 7.58 (s,1H), 7.47-7.35 (m, 3H), 6.93 (d, J = 6.8 Hz, 1H), 4.60-4.53 (s, 3H),4.30-4.23 (m, 2H), 3.93 (d, J = 10 Hz, 1H), 3.71-3.63 (m, 2H), 2.40-2.39(m, 2H), 1.38-1.32 (m, 9H). Calculated (M + H): 518.12; Found (M + 1):518.1. HPLC purity 98.54% 80

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-oxo-2-(5-azaspiro[2.3]hexan- 5- yl)ethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 7.80-7.78 (m, 2H), 7.66 (s, 1H), 7.52-7.47(m, 2H), 6.96 (d, J = 7.2 Hz, 1H), 4.60 (s, 2H), 4.24 (s, 2H), 3.91 (s,2H), 0.63 (d, J = 6 Hz, 4H). Calculated (M + H): 437.09; Found (M + H):437.1. HPLC purity: 99.84% 81

3-(3-chloro-4- fluorophenyl)-5-(2- (3-fluoro-3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 7.63-7.60 (m, 2H), 8.48 (d, J = 7.2 Hz, 1H),7.42- 7.35 (m, 2H), 6.95 (d, J = 7.2 Hz, 1H), 4.87-4.69 (m, 2H), 4.62(s, 2H), 4.49-4.34 (m, 2H), 4.12-3.95 (m, 2H). Calculated (M + H):427.04; Found (M + 1): 427.0. HPLC purity 98.33% 82

3-(3,4- dichlorophenyl)-5- (2-(3-fluoro-3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 7.67 (d, J = 1.6 Hz, 1H), 7.64 (s, 1H), 7.59 (d,J = 8.0 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.42-7.40 (dd, J = 2.0 Hz,8.4 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 4.87-4.69 (m, 2H), 4.63 (s, 2H),4.49-4.34 (m, 2H), 4.12-3.95 (m, 2H). Calculated (M + H): 443.03; Found(M + 1): 443.0. HPLC purity 99.75% 83

5-(2-(3-fluoro-3- (fluoromethyl) azetidin-1-yl)-2- oxoethy1)-3-(4-fluoro-3- (trifluoromethyl) phenyl)thieno[3,2- c]pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm); 7.78 (brs, 2H), 7.67 (s, 1H), 7.75-7.46(m, 2H), 6.97 (d, J = 6.8 Hz, 1H), 4.86-4.68 (m, 2H), 4.62 (s, 2H),4.48-4.34 (m, 2H), 4.11-3.94 (m, 2H). Calculated (M + H): 461.07; Found(M + 1): 461.1. HPLC purity 98.26% 84

3-(6-chloro-5- methylpyridin-3-yl)- 5-(2-(3-fluoro-3- methylazetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm); 8.25 (s, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 7.49 (d, J =7.6 Hz, 1H), 6.97 (d, J = 6.8 Hz, 1H), 4.60 (s, 2H), 4.37-4.24 (m, 2H),3.97-3.92 (m, 2H), 2.34 (s, 3H), 1.57 (d, J = 22.4 Hz, 3H). Calculated(M + H): 406.07; Found (M + 1): 406.0. HPLC purity 99.43% 85

3-(6-chloro-5- methylpyridin-3-yl)- 5-(2-(3-ethyl-3-fluoroazetidin-1-yl)- 2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm); 8.25 (s, 1H), 7.84 (s, 1H), 7.66 (s, 1H),7.50 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 4.61 (s, 2H),4.33-4.24 (m, 2H), 4.00-3.86 (m, 2H), 2.34 (s, 3H), 1.91-1.80 (m, 2H),0.90 (t, J = 7.2 Hz, 3H). Calculated (M + H): 420.09; Found (M + 1):420.1. HPLC purity 99.25% 86

3-(6-chloro-5- methylpyridin-3-yl)- 5-(2-(3-fluoro-3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.26 (s, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.49(d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.87-4.69 (m, 2H), 4.62(s, 2H), 4.48-4.36 (m, 2H), 4.12-3.97 (m, 2H), 2.34 (s, 3H). Calculated(M + H): 424.06; Found (M + 1): 424.0. HPLC purity 99.25% 87

5-(2-(3-fluoro-3- methylazetidin-1- yl)-2-oxoethyl)-3-(6- fluoro-5-methylpyridin-3- yl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm); 8.05 (s, 1H), 7.87 (d, J = 10.0 Hz, 1H), 7.62 (s, 1H),7.49 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 4.60 (s, 2H),4.37-4.25 (m, 2H), 3.97- 3.92 (m, 2H), 2.55 (s, 3H), 1.57 (d, J = 22.4Hz, 3H). Calculated (M + H): 390.10; Found (M + 1): 390.1. HPLC purity99.21% 88

5-(2-(3-ethyl-3- fluoroazetidin-1-yl)- 2-oxoethyl)-3-(6- fluoro-5-methylpyridin-3- yl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm); 8.05 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.62 (s, 1H),7.49 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 6.8 Hz, 1H), 4.61 (s, 2H),4.36-4.24 (m, 2H), 4.00- 3.86 (m, 2H), 2.25 (s, 3H), 1.98-1.80 (m, 2H),0.90 (t, J = 7.2 Hz, 3H). Calculated (M + H): 404.12; Found (M + 1):404.1. HPLC purity 98.16% 89

5-(2-(3-fluoro-3- (fluoromethyl) azetidin-1-yl)- 2-oxoethyl)-3-(6-fluoro-5- methylpyridin-3- yl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm); 8.05 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.62(s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 4.87-4.69(m, 2H), 4.62 (s, 2H), 4.49-4.34 (m, 2H), 4.12-3.95 (m, 2H), 2.25 (s,3H). Calculated (M + H): 408.09; Found (M + 1): 408.1. HPLC purity98.65% 90

3-(5-chloro-6- methylpyridin-3-yl)- 5-(2-(3-fluoro-3- methylazetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm); 8.44 (s, 1H), 7.90 (s, 1H), 7.70 (s, 1H), 7.50 (d, J =7.2 Hz, 1H), 6.97 (d, J = 6.8 Hz, 1H), 4.61 (s, 2H), 4.35-4.28 (m, 2H),3.97-3.93 (m, 2H), 2.55 (s, 3H), 1.57 (d, J = 21.6 Hz, 3H). Calculated(M + H): 406.07; Found (M + 1): 406.1. HPLC purity 99.70% 91

3-(5-chloro-6- methylpyridin-3-yl)- 5-(2-(3-ethyl-3-fluoroazetidin-1-yl)- 2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm); 8.44 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 1.2Hz, 1H), 7.70 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.6 Hz,1H), 4.61 (s, 2H), 4.34-4.27 (m, 2H), 3.98-3.89 (m, 2H), 2.56 (s, 3H),1.90-1.82 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H). Calculated (M + H): 420.09;Found (M + 1): 420.1. HPLC purity 99.47% 92

3-(5-chloro-6- methylpyridin-3-yl)- 5-(2-(3-fluoro-3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)thieno[3,2- c]pyridin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm); 8.45 (s, 1H), 7.91 (s, 1H), 7.71 (s, 1H), 7.49(d, J = 6.8 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.87-4.70 (m, 2H), 4.63(s, 2H), 4.46-4.37 (m, 2H), 4.09-3.98 (m, 2H), 2.56 (s, 3H). Calculated(M + H): 424.06; Found (M + 1): 424.1. HPLC purity 99.72%

Example 93: Preparation of2-(3-(3-chloro-4-fluorophenyl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

To a stirred solution of2-(3-(3-chloro-4-fluorophenyl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide(0.04 g, 0.09 mmol) in acetone (5 mL) was added potassium carbonate(0.04 g, 028 mmol) followed by methyl iodide (0.06 mL, 0.95 mmol). Thereaction mixture was heated at 50° C. for 3 days. The reaction mixturewas filtered and the filtrate was concentrated. The crude material waspurified by column chromatography, followed by preparative HPLC(analysis method: Kinetex C18 (100 mm×4.6 mm×2.6 μm), mobile phase (A):water, mobile phase (B): acetonitrile, Flow rate: 0.75 mL/min) to affordthe title compound2-(3-(3-chloro-4-fluorophenyl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide(0.01 g, 24% yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.62-7.60 (m, 2H), 7.51-7.35 (m, 3H), 6.96-6.32 (m, 1H), 4.94 (s,2H), 4.18-4.11 (m, 2H), 3.17 (s, 3H). Calculated (M+H): 433.03; Found(M+H): 433.0. HPLC purity: 99.55%.

Example 94: Preparation of5-(2-(3-amino-3-methylazetidin-1-yl)-2-oxoethyl)-3-(3,4-dichlorophenyl)thieno[3,2-c]pyridin-4(5H)-one

To a solution of tert-butyl(1-(2-(3-(3,4-dichlorophenyl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetyl)-3-methylazetidin-3-yl)carbamate(0.13 g, 0.24 mmol) in dichloromethane (10 mL) cooled to 0° C., wasadded trifluoroacetic acid (0.2 mL, 2.49 mmol) and the reaction mixturewas stirred at room temperature for 3 h. After completion of thereaction (as monitored by TLC), the reaction mixture was concentrated,the residue was basified with saturated sodium bicarbonate solution (30mL) and extracted with dichloromethane (2×50 mL). The combined organiclayer was dried over anhydrous sodium sulphate, filtered andconcentrated. The crude product was purified by silica gel columnchromatography using 5% methanol in dichloromethane to afford the titlecompound5-(2-(3-amino-3-methylazetidin-1-yl)-2-oxoethyl)-3-(3,4-dichlorophenyl)thieno[3,2-c]pyridin-4(5H)-one(0.033 g, 33% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.67 (s, 1H), 7.63 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.47 (d, J=7.2 Hz,1H), 7.4 (d, J=6.8 Hz, 1H), 6.93 (d, J=6.8 Hz, 1H), 4.56 (s, 2H), 3.94(d, J=8 Hz, 1H) 3.88 (d, J=7.6 Hz, 1H), 3.63 (d, J=9.2 Hz, 1H), 3.57 (d,J=9.2 Hz, 1H), 2.37 (brs, 2H), 1.29 (s, 3H). Calculated (M+H): 422.05,Found (M+H): 422.0, HPLC purity: 96.09%.

TABLE 4 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 95

5-(2-(3-amino-3- methylazetidin-1-yl)- 2-oxoethyl)-3-(3- chloro-4-fluorophenyl)thieno [3,2-c]pyridin-4(5H)- one ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 7.61 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 7.6 Hz,1H), 7.44-7.36 (m, 2H), 6.93 (d, J = 7.2 Hz, 1H), 4.56 (s, 2H), 3.95 (d,J = 8.0 Hz, 1H), 3.88 (d, J = 8.0 Hz, 1H), 3.63 (d, J = 9.2 Hz, 1H),3.57 (d, J = 9.2 Hz, 1H), 2.14 (s, 2H), 1.29 (s, 3H). Calculated (M +H): 406.07, Found (M + H): 406.0. HPLC purity: 99.21% 96

5-(2-(3-amino-3- methylazetidin-1-yl)- 2-oxoethyl)-3-(4- fluoro-3-(trifluoromethyl)phenyl) thieno[3,2-c] pyridin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 7.80-7.76 (m, 2H), 7.66 (s, 1H), 7.51-7.47 (m,2H), 6.95 (d, J = 7.2 Hz, 1H), 4.56 (s, 2H), 3.95 (d, J = 8.0 Hz, 1H),3.87 (d, J = 8.4 Hz, 1H), 3.63 (d, J = 9.2 Hz, 1H), 3.57 (d, J = 9.2 Hz,1H), 2.22 (brs, 2H), 1.29 (s, 3H). Calculated (M + H): 440.1; Found (M +H): 440.1. HPLC Purity: 99.74% 97

3-(3-chloro-4- fluorophenyl)-5-(2- oxo-2-(1,6- diazaspiro[3.3]heptan- 6-yl)ethyl)thieno[3,2-c] pyridin-4(5H)-one 2,2,2-trifluoroacetate ¹H NMR(400 MHz, DMSO-d₆) δ (ppm); 9.15 (brs, 2H), 7.63- 7.60 (m, 2H),7.48-7.36 (m, 3H), 6.96 (d, J = 7.2 Hz, 1H), 4.63- 4.46 (m, 4H), 4.33(d, J = 11.2 Hz, 1H), 4.15 (d, J = 11.6 Hz, 1H), 3.76 (brs, 2H), 2.68(brs, 2H). Calculated (M + H): 418.07; Found (M + H): 418.2. HPLCpurity: 99.66%

Examples 98 and 99: Preparation of7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one&3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carbonitrile

Step-1:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one

To a solution of 3-bromothieno[3,2-c]pyridin-4(5H)-one (0.55 g, 2.17mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (0.73 g, 3.25mmol) in 1,4-dioxane:water mixture (20 mL, 4:1), potassium carbonate(0.9 g, 6.51 mmol) was added. The reaction mixture was purged with argonfor 15 minutes and PdCl₂(PPh₃)₂ (0.15 g, 0.21 mmol) was added. Then thereaction mixture was stirred at 100° C. for 18 h. The reaction mixturewas diluted with water (50 mL) and extracted with ethyl acetate (3×100mL). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated. The crude product was purified bysilica gel column chromatography using 30% ethyl acetate in hexane toafford the title compound3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one(0.74 g, 94% yield) as off-white solid. Calculated (M+H): 330; Found(M+H): 330.0.

Step-2:

Preparation of7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one

To a solution of3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one(0.78 g, 2.37 mmol) in N,N-dimethylformamide (20 mL), was addedN-bromosuccinimide (0.42 g, 2.37 mmol) and the reaction mixture wasstirred at room temperature for 18 h. Then reaction mixture was pouredinto ice cold water (100 mL), the precipitated solid was filtered anddried under suction to afford the title compound7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one(0.82 g, 85% yield) as off-white solid. Calculated (M+H): 407.9; Found(M+H): 407.0.

Step-3:

Preparation of7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one(1.5 g, 3.68 mmol) in dry acetone (80 mL) was added potassium carbonate(1.52 g, 11.05 mmol) followed by 2-chloro-1-(pyrrolidin-1-yl)ethanone(0.65 g, 4.42 mmol) at room temperature and the reaction mixture washeated at 55° C. for 18 h. The reaction mixture was filtered through thecelite, washed with acetone and the filtrate was concentrated undervacuum. The crude product was purified by silica gel columnchromatography using 40% ethyl acetate in hexane to afford the titlecompound7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(1.2 g, 63% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.89 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.71 (brs, 2H), 4.73 (s, 2H),3.45 (t, J=6.4 Hz, 2H); 3.27 3.24 (m, 2H), 1.93-1.86 (m, 2H), 1.78-1.71(m, 2H). Calculated (M+H): 519.0, Found (M+H): 519.0, HPLC purity:99.04%.

Step-4:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carbonitrile

A solution of7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.2 g, 0.38 mmol) in N,N-dimethylformamide (10 mL) was degassed withargon for 10 min. Then zinc cyanide (0.04 g, 0.34 mmol), Pd₂(dba)₃(0.007 g, 0.008 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (DPPF)(0.009 g, 0.0169 mmol) were added and the resulting mixture was stirredat 130° C. for 2 h. After completion of reaction (monitored by TLC), thereaction mixture was cooled to room temperature, diluted with water (50mL) and extracted with ethyl acetate (3×80 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The crude product was purified by silica gel columnchromatography using 40% ethyl acetate in hexane to afford the titlecompound3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carbonitrile(0.1 g, 55% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.51 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.74-7.72 (m, 2H), 4.79 (s,2H), 3.46 (t, =6.4 Hz, 2H), 3.27-3.24 (m, 2H), 1.96-1.86 (m, 2H),1.78-1.73 (m, 2H) Calculated (M+H): 466.05, Found (M+H): 466.0, HPLCpurity: 99.46%.

TABLE 5 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 100

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)- 4,5-dihydrothieno[3,2-c]pyridine-7-carbonitrile ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.50 (s, 1H),7.87 (s, 1H), 7.79-7.75 (m, 2H), 7.51 (t, J = 10.8 Hz, 1H), 4.79 (s,2H), 3.46 (t, J = 6.8 Hz, 2 H), 1.91- 1.86 (m, 2 H), 1.79-1.72 (m, 2H).2H are merged with DMSO water peak. Calculated (M + H): 450.08; Found(M + H): 450.1. HPLC purity: 98.53%

Example 101: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-7-cyclopropyl-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one

To a solution of7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.15 g, 0.28 mmol), potassium carbonate (0.11 g, 0.86 mmol) andcyclopropylboronic acid (0.037 g, 0.43 mmol) in dioxane:water mixture (8mL, 4:1) argon was purged for 10 min. Then PdCl₂(PPh₃)₂ (0.02 g, 0.02mmol) was added and the resulting mixture was stirred at 100° C. for 18h. After completion of reaction (monitored by TLC), reaction mixture wascooled to room temperature and filtered through celite. The filtrate wasconcentrated under vacuum and the crude product was purified by prepHPLC (analytical conditions: column: chemsil C18 (250 mm×4.6 mm×5μ),mobile phase (A): 0.01% ammonia in water, mobile phase (B):acetonitrile, flow rate: 1.0 mL/min, T/% B: 0/20, 10/80, 25/80, 27/20,30/20, wavelength: 220 nm) to afford the title compound3-(4-chloro-3-(trifluoromethyl)phenyl)-7-cyclopropyl-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.018 g, 12% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.86 (s, 1H), 7.72-7.67 (m, 3H), 7.31 (s, 1H), 4.68 (s, 2H), 3.45 (t,J=6.4 Hz, 2H), 3.25 (s, 2H), 1.92-1.82 (m, 3H), 1.81-1.71 (m, 2H),0.91-0.86 (m, 2H), 0.62-0.58 (m, 2H). Calculated (M+H): 481.09, Found(M+H): 481.1. HPLC purity: 99.94%.

TABLE 6 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 102

3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-7- phenylthieno[3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 7.88 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 2.8 Hz, 2H),7.66 (s, 1H), 7.60 (d, J = 7.6 Hz, 2H); 7.52-7.42 (t, J = 8 Hz, 2H),7.44 (d, J = 7.2 Hz, 1H), 4.81 (s, 2H), 3.48 (t, J = 6.8 Hz, 2H), 3.28(s, 2H), 1.92- 1.87 (m, 2H), 1.79-1.72 (m, 2H), Calculated (M + H):517.09, Found (M + H): 517.1, HPLC purity: 99.90% 103

3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-7-(pyridin-4- yl)thieno[3,2-c] pyridin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.69 (d, J = 5.6 Hz, 2H), 7.92 (s, 1H), 7.87 (s,1H), 7.80 (s, 1H), 7.72 (s, 2H); 7.64 (d, J = 6 Hz, 2H), 4.82 (s, 2H),3.48 (t, J = 6.4 Hz, 2H), 3.289 (s, 2H), 1.94-1.894 (m, 2H), 1.87-1.72(m, 2H), Calculated (M + H): 518.08, Found (M + H): 518.1, HPLC purity:99.87% 104

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-7- phenylthieno[3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 7.80- 7.77 (m, 2H), 7.70 (s, 1H), 7.65 (s, 1H), 7.60(d, J = 7.6 Hz, 2H), 7.54-7.47 (m, 3H), 7.43 (t, J = 7.2 Hz, 1H), 4.81(s, 2H), 3.47 (t, J = 6.8 Hz, 2H), 3.35-3.26 (m, 2H), 1.94-1.87 (m, 2H),1.79- 1.72 (m, 2H). Calculated (M + H): 501.12; Found (M + H): 501.1.HPLC purity: 99.77% 105

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-7-(pyridin-4- yl)thieno[3,2-c] pyridin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.80 (d, J = 6.4 Hz, 2H), 8.08 (s, 1H), 7.90 (d,J = 5.2 Hz, 2H), 7.80-7.76 (m, 3H), 7.51 (t, J = 10 Hz, 1H), 4.84 (s,2H), 3.50-3.47 (m, 2H), 3.27 (t, J = 6.8 Hz, 2H), 1.93-1.88 (m, 2H),1.79- 1.73 (m, 2H). Calculated (M + H): 502.11, Found (M + H): 502.1.HPLC purity: 99.82%

Example 106: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-7-methyl-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one

To a solution of7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.15 g, 0.28 mmol) and potassium carbonate (0.199 g, 1.44 mmol) indioxane (12 mL) argon was purged for 10 minutes. Then trimethylboroxine(0.04 mL, 0.28 mmol), Pd(PPh₃)₄ (0.05 g, 0.04 mmol) were added and theresulting mixture was stirred at 100° C. for 18 h. After completion ofreaction (monitored by TLC), the reaction mixture was cooled to roomtemperature and filtered through celite. The filtrate was concentratedunder vacuum and the crude product was purified by prep HPLC (analyticalconditions: column chemsil C18 (250 mm×4.6 mm×50, mobile phase (A):0.01% ammonia in water, mobile phase (B): acetonitrile, flow rate: 1.0mL/min, T/% B: 0/20, 12/80, 25/80, 27/20, 30/20, wavelength: 220 nm) toafford the title compound3-(4-chloro-3-(trifluoromethyl)phenyl)-7-methyl-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.033 g, 25% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.86 (s, 1H), 7.73-7.67 (m, 3H), 7.33 (s, 1H), 4.69 (s, 2H), 3.46 (1,J=6.4 Hz, 2H); 3.27 (s, 2H), 2.22 (s, 3H), 1.92-1.86 (m, 2H), 1.78-1.71(m, 2H). Calculated (M+H): 455.07, Found (M+H): 455.1, HPLC purity:99.85%.

TABLE 7 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 107

3-(4-fluoro-3- (trifluoromethyl) phenyl)-7-methyl-5-(2-oxo-2-(pyrrolidin- 1-yl)ethyl)thieno[3,2-c] pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 7.79-7.75 (m, 2H), 7.68 (s, 1H), 7.48(t, J = 10 Hz, 1H), 7.33 (s, 1H), 4.69 (s, 2H), 3.46 (t, J = 6.4 Hz,2H), 3.27- 3.24 (m, 2H), 2.22 (s, 3H), 1.89 (t, J = 6.8 Hz, 2H), 1.75(t, J = 6.4 Hz, 2H). Calculated (M + H): 439.10; Found (M + H): 439.1.HPLC purity: 99.71%

Examples 108 and 109: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carboximidamide&3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(1,2,4-oxadiazol-3-yl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carboximidamide

To a stirred solution of hydroxylamine hydrochloride (0.23 g, 3.33 mmol)in ethanol (20 mL) was added triethylamine (0.9 mL, 6.67 mmol) andstirred for 10 minutes. Then3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carbonitrile(1.0 g, 2.22 mmol) was added and the reaction mixture was stirred at 65°C. for 2 h. The reaction mixture was concentrated and the residue waswashed with hexane followed by 5% methanol in dichloromethane and driedunder vacuum to afford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carboximidamide(0.9 g, 83% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):9.91 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=6 Hz, 2H), 7.64 (s, 1H), 7.46 (t,J=10 Hz, 1H), 5.77 (s, 2H), 4.72 (s, 2H), 3.48 (t, J=6.4 Hz, 2H),3.32-3.27 (m, 2H), 1.96-1.87 (m, 2H), 1.79-1.74 (m, 2H). Calculated(M+H): 483.10; Found (M+H): 483.1. HPLC purity: 99.02%.

Step-2:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(1,2,4-oxadiazol-3-yl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carboximidamide(0.1 g, 0.20 mmol) in triethylorthoformate (5 mL) was addedp-toluenesulfonic acid (0.017 g, 0.10 mmol) and the reaction mixture wasstirred at room temperature for 16 h. The reaction mixture wasconcentrated and the residue was purified by silica gel columnchromatography using 5% methanol in dichloromethane. The obtainedmaterial was again washed with water, hexane and dried under high vacuumto get the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(1,2,4-oxadiazol-3-yl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.075 g, 74% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):9.74 (s, 1H), 8.50 (s, 1H), 7.87 (s, 1H), 7.85-7.77 (m, 2H), 7.50 (t,J=8.8 Hz, 1H), 4.94 (s, 2H), 3.48 (t, J=6.4 Hz, 2H), 3.32-3.22 (m, 2H),1.94-1.88 (m, 2H), 1.86-1.73 (m, 2H). Calculated (M+H): 393.09; Found(M+H): 393.1. HPLC purity: 99.84%.

TABLE 8 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 110

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-N- hydroxy-4-oxo-4,5- dihydrothieno[3,2-c] pyridine-7-carboximidamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.91 (s, 1H), 7.98(s, 1H), 7.74 (d, J = 6.8 Hz, 2H), 7.65 (s, 1H), 7.46 (t, J = 10 Hz,1H), 5.77 (s, 2H), 5.5-5.2 (m, 1H), 4.89-4.69 m, 2H), 3.80- 3.32 (m,4H), 2.30-2.21 (m, 2H). Calculated (M + H): 501.09; Found (M + H):501.1. HPLC purity: 97.01%

Examples 111 and 112: Preparation3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one&3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(pyrrolidin-1-ylmethyl)thieno[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.05 g) in tetrahydrofuran (8 mL) was added paraformaldehyde (0.05 g)followed by concentrated hydrochloric acid (0.2 mL) and the reactionmixture was stirred at 50° C. for 18 h. The reaction mixture wasconcentrated under vacuum. The crude product was purified by silica gelcolumn chromatography using 5% methanol in dichloromethane to afford thetitle compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one(0.012 g, 22% yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.78-7.76 (m, 2H), 7.68 (s, 1H), 7.50-7.45 (m, 2H), 5.47-5.23 (m,2H), 4.87-4.68 (m, 2H), 4.48 (d, J=4.4 Hz, 2H); 3.86-3.27 (m, 4H),2.30-1.90 (m, 2H), Calculated (M+H): 473.09, Found (M+H): 473.2. HPLCpurity: 98.14%.

Step-2:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehyde

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one(0.045 g, 0.09 mmol) in dioxane (8 mL) was added manganese dioxide(0.082 g, 0.95 mmol) and the reaction mixture was stirred at 80° C. for1.5 h. The reaction mixture was filtered through celite, washed withethyl acetate and the filtrate was concentrated under vacuum. The crudeproduct was purified by silica gel column chromatography using 5%methanol in dichloromethane to afford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehyde(0.035 g, 79% yield) as a yellow solid. Calculated (M+H): 471.07, Found(M+H): 471.1.

Step-3:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(pyrrolidin-1-ylmethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehyde(0.1 g, 0.21 mmol) in dichloromethane (20 mL) was added acetic acid(0.06 mL, 10.63 mmol) followed by pyrrolidine (0.1 mL, 1.27 mmol) andthe reaction mixture was stirred at room temperature for 30 minutes.Sodium triacetoxyborohydride (0.225 g, 10.63 mmol) was added and thereaction mixture was stirred at room temperature for 18 h. The reactionmixture was diluted with saturated sodium bicarbonate solution (30 mL)and extracted with dichloromethane (3×60 mL). The combined organic layerwas dried over anhydrous sodium sulfate, filtered and evaporated toafford the crude product, which was purified by prep HPLC (analyticalconditions: column: chemsil C18 (250 mm×4.6 mm×50, mobile phase (A):0.01% ammonia in water, mobile phase (B): acetonitrile, flow rate: 1.0mL/min, T/% B: 0/20, 10/80, 25/80, 27/20, 30/20, wavelength: 220 nm) toafford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(pyrrolidin-1-ylmethyl)thieno[3,2-c]pyridin-4(5H)-one(0.024 g, 21% yield) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ (ppm):7.70 (d, J=6.4 Hz, 2H), 7.20-7.15 (m, 3H), 5.39-5.17 (m, 1H), 5.00-4.91(m, 1H), 4.49-4.37 (m, 1H); 3.92-3.79 (m, 2H), 3.77-3.49 (m, 4H), 2.58(s, 4H), 2.40-2.03 (m, 2H), 1.80 (s, 4H). Calculated (M+H): 526.15;Found (M+1): 526.3. HPLC purity: 99.93%.

Example 113: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carboximidamide

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carboximidamide(0.3 g, 0.62 mmol) in acetic acid (20 mL) was added acetic anhydride(0.06 mL, 0.68 mmol) and the reaction mixture was stirred at roomtemperature for 30 min. Then triethyl silane (0.02 mL, 0.13 mmol),palladium chloride (0.01 g, 0.0001 mmol) were added and the reactionmixture was stirred at 75° C. for 2 h. The reaction mixture was cooledto room temperature and the pH was adjusted to 7 by adding saturatedsodium bicarbonate solution. The precipitated solid was filtered. Thesolid was dissolved in 5% methanol in dichloromethane, dried overanhydrous sodium sulfate and filtered through celite bed. The filtratewas evaporated to get the crude compound which was washed with n-pentaneand diethyl ether and dried under vacuum to get the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydrothieno[3,2-c]pyridine-7-carboximidamide(0.038 g, 13% yield) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.08 (s, 1H), 7.73 (d, J=7.2 Hz, 2H), 7.62 (s, 1H), 7.45 (t, J=10.4 Hz,1H), 7.06 (brs, 1H), 6.14 (brs, 2H), 4.72 (s, 2H), 3.49 (t, J=6.8 Hz,2H), 1.94-1.87 (m, 2H), 1.79-1.74 (m, 2H). 2H are merged with DMSO waterpeak. Calculated (M+H): 467.11; Found (M+H): 467.1. HPLC purity: 98.81%.

Example 114: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one

To a solution of 3-bromothieno[3,2-c]pyridin-4(5H)-one (0.55 g, 2.17mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (0.73 g, 3.25mmol) in 1,4-dioxane:water mixture (20 mL, 4:1), potassium carbonate(0.9 g, 6.51 mmol) was added. The reaction mixture was purged with argonfor 15 min and bis(triphenylphosphine)palladium chloride [PdCl₂(PPh₃)₂](0.15 g, 0.21 mmol) was added. Then the reaction mixture was stirred at100° C. for 18 h. The reaction mixture was diluted with water (50 mL)and extracted with ethyl acetate (3×100 mL). The combined organic layerwas dried over anhydrous sodium sulphate, filtered and concentrated. Thecrude product was purified by silica gel column chromatography using 30%ethyl acetate in hexane to afford the title compound3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one(0.74 g, 94% yield) as off-white solid. Calculated (M+H): 330; Found(M+H): 330.0.

Step-2:

Preparation of7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one

To a solution of3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one(4.23 g, 13.51 mmol) in N,N-dimethylformamide (60 mL), was addedN-bromosuccinimide (2.39 g, 13.51 mmol) and the reaction mixture wasstirred at room temperature for 1 h. Then reaction mixture was pouredinto ice cold water (100 mL), the precipitated solid was filtered anddried under suction to afford the title compound7-bromo-3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one(0.82 g, 85% yield) as off-white solid. Calculated (M+H): 391.93; Found(M+H): 391.9.

Step-3:

Preparation of4-(benzyloxy)-7-bromo-3-(4-fluoro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridine

To a solution of3-(4-chloro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one(4.1 g, 10.73 mmol) in tetrahydrofuran (50 mL) were added silvercarbonate (3.88 g, 13.98 mmol), benzyl bromide (1.6 mL, 12.87 mmol) andthe reaction mixture was stirred at 85° C. for 2 h. The reaction mixturewas diluted with water (50 mL) and extracted with ethyl acetate (3×100mL). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated to afford the title compound4-(benzyloxy)-7-bromo-3-(4-fluoro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridine(0.7 g, 72.0% yield) as pale yellow solid. Calculated (M+H): 481.98;Found (M+H): 482.0.

Step-4:

Preparation of4-(benzyloxy)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridine

To a solution of4-(benzyloxy)-7-bromo-3-(4-fluoro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridine(0.75 g, 1.43 mmol) in toluene (20 mL), was added sodium tertiarybutoxide (0.44 g, 4.61 mmol) and the solution was purged with argon for10 min. Then pyrrolidine (0.3 mL, 3.58 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.093 g, 0.073 mmol) andtris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] (0.07 g, 0.076mmol) were added and the resulting mixture was stirred at 120° C. for 18h. The reaction mixture was cooled to room temperature, diluted withwater (50 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layer was dried over anhydrous sodium sulphate, filtered andconcentrated under vacuum. The crude product was purified by silica gelcolumn chromatography using 10% ethyl acetate in hexane to afford thetitle compound4-(benzyloxy)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridine(0.55 g, 75% yield) as pale yellow solid. Calculated (M+H): 473.12;Found (M+H): 473.1.

Step-5:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridin-4(5H)-one

To4-(benzyloxy)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridine(0.15 g, 0.31 mmol)trifluoroacetic acid (5 mL) was added at 0° C. andthe reaction mixture was stirred at room temperature for 30 min. Thereaction mixture was diluted with ice water (20 mL) and extracted withethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous sodium sulphate, filtered and concentrated to afford the titlecompound3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridin-4(5H)-one(0.13 g, 99.0% yield) as purple solid. Calculated (M+H): 383.08; Found(M+H): 383.1.

Step-6:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridin-4(5H)-one(0.13 g, 0.34 mmol) in dry acetone (20 mL) was added potassium carbonate(0.23 g, 1.67 mmol) followed by 2-chloro-1-(pyrrolidin-1-yl)ethanone(0.075 g, 0.51 mmol) at room temperature. The reaction mixture washeated at 65° C. for 2 h. The reaction mixture was filtered and thefiltrate was concentrated under vacuum. The crude product was purifiedby silica gel column chromatography using 5% methanol in dichloromethaneto afford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-7-(pyrrolidin-1-yl)thieno[3,2-c]pyridin-4(5H)-one(0.006 g, 4.0% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.75 (d, J=5.6 Hz, 2H), 7.69 (s, 1H), 7.47 (t, J=9.2 Hz, 1H), 7.04 (s,1H), 4.68 (s, 2H), 3.45 (t, J=6.8 Hz, 2H), 3.11 (s, 4H), 1.89 (t, 6H),1.78-1.73 (q, 2H). 2H merged with DMSO water. Calculated (M+H): 494.14,Found (M+H): 494.1. HPLC purity: 99.80%.

TABLE 9 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 115

7-(azetidin-1-yl)-3- (4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2-c] pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 7.77 (d, J = 6.4 Hz, 2H), 7.7 (s, 1H),7.46 (t, J = 9.2 Hz, 1H), 6.82 (s, 1H), 5.48-5.23 (m, 1H), 4.83-4.66 (m,2H), 3.84-3.20 (m, 8H), 2.30-1.85 (m, 4H). Calculated (M + H): 498.12,Found (M + H): 498.1, HPLC purity: 99.09%

Example 116: Preparation of7-((dimethylamino)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of7-(chloromethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one(0.1 g) in dichloromethane (10 mL) was added thionyl chloride (3 mL) at0° C. and the reaction mixture was stirred at room temperature for 18 h.The reaction mixture was concentrated under vacuum to afford the titlecompound7-(chloromethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.12 g, crude) as a colourless liquid. The crude was as such taken forthe next step without purification.

Step-2:

Preparation of7-((dimethylamino)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred suspension of potassium carbonate (0.10 g, 0.732 mmol) inacetonitrile (5 mL) was added 2M dimethylamine in tetrahydrofuran (1.2mL, 2.44 mmol) and the reaction mixture was stirred at room temperaturefor 10 min. Then a solution of7-(chloromethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.12 g, 0.244 mmol, crude) in acetonitrile (5 mL) was added and thereaction mixture was stirred in orbital shaker at room temperature for18 h. The reaction mixture was filtered, the filtrate was concentratedand the crude product was purified by silica gel column chromatographyusing 6% methanol in dichloromethane to afford the title compound7-((dimethylamino)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.009 g, 7% yield) as a green solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.76 (t, J=6.4 Hz, 2H), 7.64 (s, 1H), 7.47 (t, J=10 Hz, 1H), 7.42 (s,1H), 5.48-5.23 (m, 1H); 4.86-4.68 (m, 2H), 3.82-3.47 (m, 4H), 3.44 (s,2H), 2.47-2.19 (m, 2H), 2.16 (s, 6H), Calculated (M+H): 500.1, Found(M+H): 500.1. HPLC purity: 96.29%.

Example 117: Preparation of7-((diethylamino)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one2,2,2-trifluoroacetate

To a stirred solution of potassium carbonate (0.033 g, 0.24 mmol) inacetonitrile (8 mL) was added diethyl amine (1.2 mL, 2.44 mmol) and thereaction mixture was stirred at room temperature for 10 min. Then asolution of7-(chloromethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.06 g, crude) in acetonitrile (5 mL) was added and the reactionmixture was stirred at room temperature for 5 h. The reaction mixturewas filtered, the filtrate was concentrated and the crude product waspurified by preparative HPLC (analysis method: kinetex C18 (100 mm×4.6mm×2.6 mm), mobile phase (A): 0.01% TFA in water, mobile phase (B):acetonitrile, flow rate: 0.75 ml/min) to afford the title compound7-((diethylamino)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.007 g, 10% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.42 (brs, 1H), 7.81-7.76 (m, 4H), 7.50 (t, J=10 Hz, 1H),5.49-5.24 (m, 1H); 4.94-4.76 (m, 2H), 4.35 (s, 2H), 3.89-3.59 (m, 4H),3.20 (brs, 4H), 2.30-1.952 (m, 2H), 1.28 (s, 6H). Calculated (M+H):528.1, Found (M+H): 528.2. HPLC purity: 99.52%.

Example 118: Preparation of7-(azetidin-1-ylmethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of potassium carbonate (0.084 g, 0.61 mmol) inacetonitrile (10 mL) was added azetidine hydrochloride (0.095, 1.02mmol) and the reaction mixture was stirred at room temperature for 10min. Then a solution of7-(chloromethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.1 g, 0.204 mmol, crude) in acetonitrile (5 mL) was added and thereaction mixture was stirred at room temperature for 18 h. The reactionmixture was filtered, the filtrate was concentrated and the crudeproduct was purified by silica gel column chromatography using 5%methanol in dichloromethane to afford the title compound7-(azetidin-1-ylmethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.006 g, 5% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.77 (d, J=6 Hz, 2H), 7.64 (s, 1H), 7.46 (t, J=9.6 Hz, 1H), 7.40 (s,1H); 5.48-5.23 (m, 1H), 4.86-4.68 (m, 2H), 3.85-3.77 (m, 2H), 3.74-3.54(m, 2H), 3.50 (s, 2H), 3.15 (s, 4H), 2.30-2.05 (m, 2H), 2.05 (t, J=6 Hz,2H). Calculated (M+H): 512.1, Found (M+H): 512.1. HPLC purity: 98.64%.

TABLE 10 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 119

3-(3-chloro-4- fluorophenyl)-5-(2- (3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7- (pyrrolidin-1- ylmethyl)thieno[3,2-c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.76 (d, J = 14.4Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.41-7.37 (m, 2H), 5.49-5.25 (m, 1H),4.94-4.76 (m, 2H), 4.43-4.29 (m, 2H), 4.07-3.71 (m, 3H), 3.66-3.25 (m,7H), 2.31-1.86 (m, 4H). Calculated (M + H): 492.12; Found (M + H):492.1; HPLC purity: 99.42% 120

3-(3-chloro-4- fluorophenyl)-7- ((dimethylamino) methyl)-5-(2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2-c] pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 7.60 (d, J = 6.8 Hz, 1H), 7.57 (s, 1H),7.41-7.34 (m, 3H), 5.50-5.22 (m, 1H), 4.82- 4.73 (m, 2H), 3.86-3.45 (m,4H), 3.37 (s, 2H), 2.25-2.02 (m, 8H). Calculated (M + H): 466.11; Found(M + H): 466.2; HPLC purity: 98.92% 121

3-(3,4- dichlorophenyl)-5- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)-7-(pyrrolidin-1- ylmethyl)thieno[3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 9.77 (brs, 1 H), 7.78 (s, 2H), 7.62 (t, J = 8.4 Hz,2H), 7.39 (d, J = 7.6 Hz, 1H), 5.49- 5.24 (m, 1H), 4.94-4.75 (m, 2H),4.42 (d, J = 4.4 Hz, 2H), 3.87-3.19 (m, 8H), 2.30-1.86 (m, 6H):Calculated (M + H): 508.1, Found (M + H): 508.1, HPLC purity: 99.74% 122

7-(azetidin-1- ylmethyl)-3-(3,4- dichlorophenyl)-5- (2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2-c] pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 7.65 (s, 1H), 7.62 (s, 1H), 7.58 (d, J =8.4 Hz, 1H), 7.40 (s, 2 H), 5.35-5.23 (m, 1H), 4.86-4.72 (m, 2H), 3.75(s, 2H), 3.60-3.49 (m, 4H), 3.16- 3.12 (m, 6H), 2.30-1.98 (m, 2H).Calculated (M + H): 494.08, Found (M + H): 494.2, HPLC purity: 97.48%123

3-(3,4- dichlorophenyl)-7- ((dimethylamino) methyl)-5-(2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2-c] pyridin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 9.70 (brs, 1H), 7.75 (d, J = 12.0 Hz,2H), 7.65 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H),5.49-5.24 (m, 1H), 4.94-4.76 (m, 2H), 4.34 (s, 2H), 3.90-3.11 (m, 4H),2.82 (brs, 6H), 2.30-1.95 (m, 2H). Calculated (M + H): 482.08, Found(M + H): 482.3, HPLC purity: 99.17% 124

7-(azetidin-1- ylmethyl)-3-(3- chloro-4- fluorophenyl)-5-(2-(3-fluoropyrrolidin- 1-yl)-2- oxoethyl)thieno[3,2-c] pyridin-4(5H)-one¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.61-7.58 (m, 2H), 7.39-7.34 (m, 3H),5.48-5.23 (m, 1H), 4.86-4.69 (m, 2H), 3.86-3.3 (m, 6H), 3.14 (t, J = 7.2Hz, 4H), 2.3-1.9 (m, 4H). Calculated (M + H): 478.11, Found (M + H):478.1. HPLC purity: 99.82% 125

3-(3-chloro-4- fluorophenyl)-7-((3- fluoroazetidin-1-yl)methyl)-5-(2-(3- fluoropyrrolidin-1- yl)-2- oxoethyl)thieno[3,2-c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.61-7.59 (m, 2H),7.43-7.34 (m, 3H), 5.49-5.10 (m, 2H), 4.87-4.69 (m, 2H), 3.86-3.65 (m,1H), 3.62-3.49 (m, 6H), 3.46-3.36 (m, 1H), 3.28-3.14 (m, 2H), 2.24-2.21(m, 1H), 2.10-2.06 (m, 1H). Calculated (M + H): 496.10, Found (M + H):496.1. HPLC purity: 99.39%

Example 126: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(methoxymethyl)thieno[3,2-c]pyridin-4(5H)-one

To a suspension of sodium hydride (60% dispersion in oil) (0.06 g, 0.67mmol) in tetrahydrofuran cooled to 0° C., was added3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one(0.08 g, 0.16 mmol) portion wise and the reaction mixture stirred at 0°C. for 15 min. Then methyl iodide (0.1 mL, 1.69 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h.The reaction mixture was quenched with cold water (20 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and evaporated to afford the crudeproduct which was purified by silica gel column chromatography using 3%methanol in dichloromethane to afford3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(methoxymethyl)thieno[3,2-c]pyridin-4(5H)-one(0.022 g, 26% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 7.69 (brs, 2H), 7.25-7.17 (m, 3H), 5.3-5.18 (m, 1H), 4.97-4.91(m, 1H), 4.49-4.38 (m, 3H), 3.89-3.49 (m, 4H), 3.42 (s, 3H), 2.37-2.10(m, 2H). Calculated (M+H): 487.1, Found (M+H): 487.1, HPLC purity:99.86%.

Table 11: The following compound was prepared by the method describedabove:

TABLE 11 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 127

7-(ethoxymethyl)- 3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno [3,2-c]pyridin-4(5H)- one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.79-7.77 (m, 2H), 7.69 (s, 1H),7.53-7.46 (m, 2H), 5.48-5.23 (m, 1H), 4.87-4.69 (m, 2H), 4.47 (s, 2H),3.86-3.27 (m, 6H), 2.30- 1.91 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H).Calculated (M + H): 501.12; Found (M + H): 501.2. HPLC purity: 98.45%128

3-(3-chloro-4- fluorophenyl)-5- (2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-7- (methoxymethyl) thieno[3,2-c]pyridin- 4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.51 (d, J = 6.0 Hz, 1H), 7.36 (brs,1H), 7.21 (brs, 1H), 7.16-7.11 (m, 2 H), 5.38-5.17 (m, 1H), 5.01-4.91(m, 1H), 4.48-4.38 (m, 3H), 3.92-3.41 (m, 7H), 2.36-2.26 (m, 1H),2.03-1.99 (m, 1H). Calculated (M + H): 453.08, Found (M + H): 453.1,HPLC purity: 98.28% 129

3-(3-chloro-4- fluorophenyl)-5- (2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-7- (hydroxymethyl) thieno[3,2-c]pyridin- 4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.61-7.59 (m, 2H), 7.44-7.34 (m, 3H),5.48-5.35 (m, 2H), 4.87-4.69 (m, 2H), 4.48 (d, J = 5.2 Hz, 2H), 3.86-3.27 (m, 4H), 2.24-1.94 (m, 2H). Calculated (M + H): 439.06, Found (M +H): 439.0. HPLC purity: 96.17% 130

3-(3-chloro-4- fluorophenyl)-7- (ethoxymethyl)-5- (2-(3-fluoropyrrolidin-1- yl)-2- oxoethyl)thieno [3,2-c]pyridin-4(5H)- one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 7.62-7.60 (m, 2H), 7.52 (s, 1H),7.43-7.34 (m, 2H), 5.48-5.23 (m, 1H), 4.87- 4.69 (m, 2H), 4.45 (s, 2H),3.86-3.27 (m, 6H), 2.24-1.94 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H).Calculated (M + H): 467.09, Found (M + H): 467.1. HPLC purity: 99.1% 131

3-(3,4- dichlorophenyl)-5- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)-7-(hydroxymethyl) thieno[3,2-c]pyridin- 4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.65 (s, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.40(d, J = 8.4 Hz, 1H), 5.48-5.34 (m, 2H), 4.87-4.69 (m, 2H), 4.48 (d, J =4.8 Hz, 2H), 3.86-3.32 (m, 4H), 2.24- 1.94 (m, 2H). Calculated (M + H):455.03, Found (M + H): 455.2, HPLC purity: 99.15% 132

3-(3,4- dichlorophenyl)-5- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)-7-(methoxymethyl) thieno[3,2-c]pyridin- 4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.57 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0Hz, 1H), 7.23 (d, J = 6.0 Hz, 1H), 7.18 (s. 1H), 5.30- 5.17 (m, 1H),5.02-4.93 (m, 1H), 4.48-4.37 (m, 3H), 3.88- 3.41 (m, 6H), 2.4-2.0 (m,2H). Calculated (M + H): 469.05, Found (M + H): 469.0, HPLC purity:99.17%

Example 133: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)thieno[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.05 g) in tetrahydrofuran (8 mL), was added paraformaldehyde (0.05 g)followed by concentrated hydrochloric acid (0.2 mL) and the reactionmixture was stirred at 50° C. for 18 h. The reaction mixture wasconcentrated under vacuum. The crude product was purified by silica gelcolumn chromatography using 5% methanol in dichloromethane to afford thetitle compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one(0.012 g, 22% yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.78-7.76 (m, 2H), 7.68 (s, 1H), 7.50-7.45 (m, 2H), 5.47-5.23 (m,2H), 4.87-4.68 (m, 2H), 4.48 (d, J=4.4 Hz, 2H); 3.86-3.27 (m, 4H),2.30-1.90 (m, 2H), Calculated (M+H): 473.09, Found (M+H): 473.2. HPLCpurity: 98.14%.

Step-2:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehyde

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(hydroxymethyl)thieno[3,2-c]pyridin-4(5H)-one(1.82 g, 3.85 mmol) in dioxane (50 mL) was added manganese dioxide (3.35g, 38.55 mmol) and the reaction mixture was stirred at 80° C. for 1.5 h.The reaction mixture was filtered through celite, washed with ethylacetate and the filtrate was concentrated under vacuum. The crudeproduct was purified by silica gel column chromatography using 5%methanol in dichloromethane to afford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehyde(1.53 g, 84% yield) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 9.78 (s, 1H), 8.58 (d, J=2.4 Hz, 1H), 7.82 (s, 1H), 7.79-7.75 (m,2H), 7.50 (t, J=9.2 Hz, 1H); 5.7-5.24 (m, 1H), 5.04-4.86 (m, 2H),3.90-3.79 (m, 2H); 3.77-3.62 (m, 2H), 2.47-2.07 (m, 2H), Calculated(M+H): 471.0; Found (M+1): 471.0. HPLC purity: 98.87%.

Step-3:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(1-hydroxyethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehyde(0.1 g, 0.21 mmol) in tetrahydrofuran (8 mL), was added 3M methylmagnesium bromide in ether (0.13 mL, 0.42 mmol) at −78° C. drop wise andthe reaction mixture was stirred at −78° C. for 2 h. The reactionmixture was quenched with saturated ammonium chloride solution (15 mL)and extracted with ethyl acetate (3×60 mL). The combined organic layerwas dried over anhydrous sodium sulfate, filtered and evaporated toafford the crude product, which was purified by silica gel columnchromatography using 4% methanol in dichloromethane to afford the titlecompound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(1hydroxyethyl)thieno[3,2-c]pyridin-4(5H)-one(0.06 g, 60% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm):7.70 (d, J=6 Hz, 2H), 7.66 (s, 1H), 7.49-7.43 (m, 2H), 5.49-5.23 (m,2H), 4.88-4.68 (m, 3H); 3.82-3.48 (m, 4H), 2.30-2.05 (m, 2H), 1.44 (d,J=6.8 Hz, 3H). Calculated (M+H): 487.1; Found (M+1): 487.3. HPLC purity:99.41%.

Step-4:

Preparation of7-acetyl-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(1hydroxyethyl)thieno[3,2-c]pyridin-4(5H)-one(0.05 g, 0.10 mmol) in dichloromethane (8 mL), was added manganesedioxide (0.089 g, 1.02 mmol) and the reaction mixture was stirred at 50°C. for 30 minutes. The reaction mixture was filtered through celite,washed with ethyl acetate and the filtrate was concentrated undervacuum. The crude product was purified by silica gel columnchromatography using 5% methanol in dichloromethane to afford the titlecompound7-acetyl-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.045 g, 91% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 8.74 (s, 1H), 7.76 (d, J=4.4 Hz, 3H), 7.48 (t, J=9.6 Hz, 1H);5.38-5.03 (m, 1H), 4.99-4.85 (m, 2H), 3.85-3.76 (m, 2H), 3.63-3.27 (m,2H), 2.47 (s, 3H) 2.30-2.09 (m, 2H). Calculated (M+H): 485.0; Found(M+1): 485.1. HPLC purity: 99.65%.

Step-5:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution7-acetyl-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.21 g, 0.43 mmol) in tetrahydrofuran (15 mL), was added 3M methyllithium in diethoxyethane (0.57 mL, 1.73 mmol) at 0° C. drop wise andthe reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was quenched with saturated ammonium chloride solution(30 mL) and extracted with ethyl acetate (3×80 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedto afford the crude product, which was purified by prep HPLC (analyticalconditions: column: chemsil C₁₈ (250 mm×4.6 mm×5μ), mobile phase (A):

0.1% ammonia in water, mobile phase (B): acetonitrile, flow rate: 1.0mL/min, T/% B: 0/20, 10/80, 25/80, 27/20, 30/20) to afford the titlecompound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)thieno[3,2-c]pyridin-4(5H)-one(0.23 g, 10% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm):7.74 (d, J=5.6 Hz, 2H), 7.65 (s, 1H), 7.45 (t, J=10 Hz, 1H), 7.39 (s,1H), 5.48-5.36 (m, 1H), 5.23 (s, 1H), 4.86-4.68 (m, 2H); 3.84-3.48 3.51(m, 4H), 2.47-2.07 (m, 2H). 1.52 (s, 6H), Calculated (M+H): 501.1; Found(M+1): 501.1. HPLC purity: 99.40%.

Example 134: Preparation of(E)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehydeoxime

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehyde(0.1 g, 0.21 mmol) in methanol (10 mL) were added hydroxylaminehydrochloride (0.073 g, 1.06 mmol), sodium acetate (0.139 g, 1.70 mmol)and the reaction mixture was stirred at room temperature for 5 h. Thereaction mixture was concentrated under vacuum. The residue was dilutedwith dichloromethane (100 mL) and washed with water (30 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedto afford the crude product which was purified by silica gel columnchromatography using 5% methanol in dichloromethane to afford the titlecompound(E)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbaldehydeoxime (0.05 g, 48% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.31 (s, 1H), 8.16 (s, 1H), 7.84 (d, J=4 Hz, 1H), 7.77 (d, J=8.8Hz, 3H), 7.48 (t, J=9.6 Hz, 1H), 5.48-5.23 (m, 1H); 4.92-4.76 (m, 2H),3.88-3.46 (m, 4H), 2.30-2.06 (m, 2H), Calculated (M+H): 486.0, Found(M+H): 486.1. HPLC purity: 98.19%.

Example 135: Preparation of(Z)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(1-(hydroxyimino)ethyl)thieno[3,2-c]pyridin-4(5H)-one

To a stirred solution of7-acetyl-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,2-c]pyridin-4(5H)-one(0.1 g, 0.20 mmol) in methanol (10 mL) were added hydroxylaminehydrochloride (0.143 g, 2.06 mmol), sodium acetate (0.135 g, 1.64 mmol)and the reaction mixture was stirred at 65° C. for 18 h. The reactionmixture was concentrated under vacuum. The residue was diluted withdichloromethane (100 mL) and washed with water (30 ml). The organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedto afford the crude product which was purified by silica gel columnchromatography using 4% methanol in dichloromethane to afford the titlecompoundZ)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-7-(1-(hydroxyimino)ethyl)thieno[3,2-c]pyridin-4(5H)-one(0.022 g, 16% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.36 (s, 1H), 7.95 (s, 1H), 7.75 (d, 6.8 Hz, 2H), 7.69 (s, 1H),7.46 (t, J=10 Hz, 1H), 5.49-5.24 (m, 1H); 4.96-4.4.79 (m, 2H), 3.83-3.56(m, 4H), 2.30-1.9 (m, 5H). Calculated (M+H): 500.1, Found (M+H): 500.1.HPLC purity: 96.72%.

Example 136: Preparation of3-chloro-5-(5-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothienopyridin-3-yl)picolinonitrile

Step-1:

Preparation of ethyl2-(3-(5-chloro-6-cyanopyridin-3-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetate

To a solution of ethyl2-(3-bromo-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetate (0.1 g, 0.31 mmol)and (5-chloro-6-cyanopyridin-3-yl)boronic acid (0.105 g, 0.39 mmol) in1,4-dioxane (10 mL), sodium carbonate (0.101 g, 0.95 mmol, 2M in water)was added. Then the reaction purged with argon for 15 minutes. ThenPd(dppf)Cl₂.DCM (0.013 g, 0.015 mmol) was added and the reaction mixturewas stirred at 80° C. for 45 minutes. Then reaction mixture was filteredthrough celite, the filtrate was diluted with ethyl acetate (100 mL) andwashed with water (2×30 mL). The organic layer was concentrated toafford the crude product which was purified by silica gel columnchromatography using 65% ethyl acetate in hexane to afford titlecompound ethyl2-(3-(5-chloro-6-cyanopyridin-3-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetate(0.1 g, 84% yield) as brownish solid. Calculated (M+H): 374.03; Found(M+H): 374.0.

Step-2:

Preparation of2-(3-(5-chloro-6-cyanopyridin-3-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)aceticacid

To a stirred solution of ethyl2-(3-(5-chloro-6-cyanopyridin-3-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetate(0.1 g, 0.26 mmol) in tetrahydrofuran: water mixture (10 mL, 1:1) wasadded lithium hydroxide monohydrate (0.056 g, 1.34 mmol) at 0° C. andthe reaction mixture was stirred at 0° C. for 15 minutes. The reactionmixture was acidified using 1.5N hydrochloric acid and extracted withethyl acetate (2×50 mL). The combined organic layer was dried overanhydrous sodium sulphate, filtered and concentrated to afford the titlecompound2-(3-(5-chloro-6-cyanopyridin-3-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)aceticacid (0.08 g, 87% yield) as brownish solid. Calculated (M+H): 346.00;Found (M+H): 346.0.

Step-3:

Preparation of3-chloro-5-(5-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)picolinonitrile

To a stirred solution of2-(3-(5-chloro-6-cyanopyridin-3-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)aceticacid (0.08 g, 0.23 mmol) and 3-fluoro-3-methylazetidine hydrochloride(0.057 g, 0.46 mmol) in dichloromethane (20 mL) was added triethylamine(0.26 mL, 1.85 mmol) at room temperature. The reaction mixture wascooled to 0° C., 1-propanephosphonic anhydride solution (T₃P) (0.26 mL,0.40 mmol, 50% in ethyl acetate) was added drop-wise and the reactionmixture was stirred at room temperature for 18 h. The reaction mixturewas diluted with water (20 mL) and extracted with dichloromethane (2×60mL). The combined organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The crude product was purifiedby silica gel column chromatography followed by preparative HPLC[analytical conditions: column: Inertsil ODS 3V (250 mm×4.6 mm×5μ),mobile phase (A): 0.1% ammonia in water, mobile phase (B): acetonitrile,flow rate: 1.0 mL/min, isocratic: (50:50)] to afford the title compound3-chloro-5-(5-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)picolinonitrile(0.03 g, 31% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm);8.77 (d, J=1.2 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H), 7.94 (s, 1H), 7.54 (d,J=7.6 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 4.63 (s, 2H), 4.36-4.28 (m, 2H),3.97-3.93 (m, 2H), 1.57 (d, J=22 Hz, 3H). Calculated (M+H): 417.05;Found (M+1): 417.1. HPLC purity 99.47%.

TABLE 12 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 137

3-chloro-5-(5-(2- (3-ethyl-3- fluoroazetidin-1- yl)-2-oxoethyl)-4-oxo-4,5- dihydrothieno [3,2-c]pyridin-3- yl)picolinonitrile ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 8.77 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 7.93 (s,1H), 7.54 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 4.64 (s, 2H),4.37-4.25 (m, 2H), 4.00-3.86 (m, 2H), 1.92-1.80 (m, 2H), 0.90 (t, J =7.6 Hz, 3H). Calculated (M + H): 431.07; Found (M + 1): 431.2. HPLCpurity 99.82% 138

3-chloro-5-(5-(2- (3-fluoro-3- (fluoromethyl) azetidin-1-yl)-2-oxoethyl)-4-oxo- 4,5- dihydrothieno [3,2-c]pyridin-3- yl)picolinonitrile¹H NMR (400 MHz, DMSO- d₆) δ (ppm); 8.77 (d, J = 1.2 Hz, 1H), 8.34 (d, J= 0.8 Hz, 1H), 7.94 (s, 1H), 7.53 (d, J = 6.8 Hz, 1H), 7.03 (d, J = 7.2Hz, 1H), 4.87-4.70 (m, 2H), 4.66 (s, 2H), 4.47-4.35 (m, 2H), 4.12-3.95(m, 2H). Calculated (M + H): 435.04; Found (M + 1): 435.2. HPLC purity99.89% 139

3-(5,6- difluoropyridin-3- yl)-5-(2-(3-fluoro- 3-methylazetidin-1-yl)-2- oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz,DMSO- d₆) δ (ppm); 8.12 (m, 2H), 7.75 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H),6.99 (d, J = 7.2 Hz, 1H), 4.62 (s, 2H), 4.38-4.25 (m, 2H), 3.98-3.93 (m,2H), 1.57 (d, J = 22 Hz, 3H). Calculated (M + H): 394.08; Found (M + 1):394.1. HPLC purity 98.32% 140

3-(2- chloropyrimidin-5- yl)-5-(2-(3-fluoro- 3-methylazetidin- 1-yl)-2-oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.82 (s, 2H), 7.86 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.01 (d, J= 7.6 Hz, 1H), 4.62 (s, 2H), 4.38-4.25 (m, 2H), 3.98-3.93 (m, 2H), 1.57(d, J = 22 Hz, 3H). Calculated (M + H): 393.05; Found (M + 1): 393.0.HPLC purity 99.94% 141

3-(2- chloropyrimidin-5- yl)-5-(2-(3-ethyl- 3-fluoroazetidin-1- yl)-2-oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.82 (s, 2H), 7.86 (s, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.01 (d, J= 7.2 Hz, 1H), 4.63 (s, 2H), 4.37-4.25 (m, 2H), 4.00-3.86 (m, 2H), 1.92-1.80 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). Calculated (M + H): 407.07;Found (M + 1): 407.1. HPLC purity 99.67% 142

3-(2- chloropyrimidin-5- yl)-5-(2-(3-fluoro- 3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 8.83 (s, 2H), 7.86 (s, 1H), 7.52 (d, J = 7.2 Hz,1H), 7.02 (d, J = 7.6 Hz, 1H), 4.87-4.70 (m, 2H), 4.64 (s, 2H),4.49-4.34 (m, 2H), 4.12- 3.95 (m, 2H). Calculated (M + H): 411.04; Found(M + 1): 411.0. HPLC purity 99.73% 143

3-(5,6- difluoropyridin-3- yl)-5-(2-(3-ethyl- 3-fluoroazetidin-1- yl)-2-oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.12-8.07 (m, 2H), 7.75 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 6.98(d, J = 7.2 Hz, 1H), 4.62 (s, 2H), 4.37- 4.25 (m, 2H), 4.00-3.86 (m,2H), 1.91-1.80 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). Calculated (M + H):408.09; Found (M + 1): 408.1. HPLC purity 99.88% 144

3-(5,6- difluoropyridin-3- yl)-5-(2-(3-fluoro- 3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 8.13-8.08 (m, 2H), 7.76 (s, 1H), 7.50 (d, J =6.8 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 4.87-4.69 (m, 2H), 4.64 (s, 2H),4.49-4.34 (m, 2H), 4.12-3.95 (m, 2H). Calculated (M + H): 412.07; Found(M + 1): 412.1. HPLC purity 99.62% 145

3-(6- chloropyrazin-2- yl)-5-(2-(3-fluoro- 3-methylazetidin- 1-yl)-2-oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.85 (s, 1H), 8.71 (s, 1H), 7.97 (s, 1H), 7.54 (d, J = 7.2 Hz,1H), 7.02 (d, J = 7.6 Hz, 1H), 4.63 (s, 2H), 4.38- 4.25 (m, 2H),3.98-3.93 (m, 2H), 1.57 (d, J = 22 Hz, 3H). Calculated (M + H): 393.05;Found (M + 1): 393.0. HPLC purity 99.36% 146

3-(6- chloropyrazin-2- yl)-5-(2-(3-fluoro- 3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 8.85 (s, 1H), 8.71 (s, 1H), 7.98 (s, 1H), 7.53(d, J = 7.2 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 4.87-4.69 (m, 2H), 4.66(s, 2H), 4.49-4.35 (m, 2H), 4.12-3.95 (m, 2H). Calculated (M + H):411.04; Found (M + 1): 411.0. HPLC purity 99.88% 147

3-(6- chloropyrazin-2- yl)-5-(2-(3-ethyl- 3-fluoroazetidin-1- yl)-2-oxoethyl)thieno [3,2-c] pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.85 (s, 1H), 8.71 (s, 1H), 7.97 (s, 1H), 7.54 (d, J = 7.6 Hz,1H), 7.02 (d, J = 7.6 Hz, 1H), 4.64 (s, 2H), 4.34- 4.27 (m, 2H),3.98-3.90 (m, 2H), 1.90-1.82 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).Calculated (M + H): 407.07; Found (M + 1): 407.1. HPLC purity 99.64%

B. Preparation of Pyrrolopyrimidinones Examples 148 and 149: Preparationof5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one&5-(4-chloro-3-(trifluoromethyl)phenyl)-7-(2-fluoroethyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

Step 1:

Preparation of 5-bromo-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

To a stirred solution of 3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (5.5 g,40.7 mmol) in N,N-dimethyl formamide (100 mL),N-(bis-trimethylsilyl)acetonitrile (18.22 g, 89.55 mmol) and N-bromosuccinimide (7.24 g, 40.7 mmol) were added and the reaction mixture wasstirred at room temperature for 2 h. The reaction mixture was quenchedwith cold water (1000 mL) and stirred for 30 minutes. The precipitatedsolid was filtered and dried under suction to afford title compound5-bromo-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (6.26 g, crude) as brownsolid. Calculated (M+H): 213.9; Found (M+H): 214.0.

Step 2:

Preparation of tert-butyl5-bromo-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-7(4H)-carboxylate

To a solution of 5-bromo-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (7.1 g,33.17 mmol) in N,N-dimethyl formamide (150 mL) were added4-dimethylaminopyridine (DMAP) (0.406 mL, 3.31 mmol)) and di-tert-butyldicarbonate [(Boc)₂O] (6.46 mL, 28.19 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 2 h. The reaction mixture was quenchedwith cold water (1000 mL) and stirred for 30 minutes. The precipitatedsolid was filtered and dried under suction to afford the title compoundtert-butyl 5-bromo-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-7(4H)-carboxylateas off white solid (8.1 g, crude). Calculated (M+H): 314.1; Found (M+H):314.0.

Step 3:

Preparation of tert-butyl5-bromo-3-(2-ethoxy-2-oxoethyl)-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-7(4H)-carboxylate

To a solution of tert-butyl5-bromo-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-7(4H)-carboxylate (4.0 g,12.73 mmol) in acetone (100 mL) were added ethyl 2-bromoacetate (4.25 g,25.47 mmol) and potassium carbonate (5.28 g, 38.19 mmol) at roomtemperature and the reaction mixture was stirred at 55° C. for 30minutes. The reaction mixture was cooled and filtered. The solid waswashed with ethyl acetate (100 mL) and the combined filtrate wasevaporated to get crude product, which was purified by silica gel columnchromatography using 50% ethyl acetate in hexane to afford tert-butyl5-bromo-3-(2-ethoxy-2-oxoethyl)-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-7(4H)-carboxylate(3.49 g, 66.7% yield) as off-white solid. Calculated (M+H): 400.04;Found (M+H): 400.0.

Step 4:

Preparation of2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-yl)aceticacid

To a solution of tert-butyl5-bromo-3-(2-ethoxy-2-oxoethyl)-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-7(4H)-carboxylate(1.5 g, 3.88 mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronic acid(1.2 g, 5.82 mmol) in 1,4-dioxane:water mixture (32 mL, 4:1), potassiumcarbonate (1.63 g, 11.68 mmol) was added. The reaction mixture waspurged with argon for 30 minutes. Then Pd(dppf)Cl₂.DCM complex (0.167 g,0.19 mmol) was added and the reaction mixture was stirred at 100° C. for16 h. The reaction mixture was cooled, diluted with water (150 mL),extracted with ethyl acetate (150 mL) and the organic layer wasdiscarded. The aqueous layer was acidified using 1.5N hydrochloric acidat 0° C., the obtained precipitate was filtered and dried under suctionto afford the title compound2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-yl)aceticacid (1.1 g, crude) as off-white solid. Calculated (M+H): 372.02; Found(M+H): 372.0.

Step 5:

Preparation of5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

To a stirred solution of2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-yl)aceticacid (0.5 g, 1.34 mmol) in dichloromethane (30 mL) were addedtriethylamine (0.94 mL, 2.69 mmol) and pyrrolidine (0.21 mL, 2.69 mmol)at room temperature. The reaction mixture was stirred for 10 minutes,then propylphosphonic anhydride solution (T₃P) (0.60 mL, 2.69 mmol, 50%in ethyl acetate) was added at 0° C. and reaction mixture was stirred atroom temperature for 16 h. The reaction mixture was diluted with water(50 mL) and extracted with dichloromethane (3×70 mL). The combinedorganic extract was dried over anhydrous sodium sulfate, filtered andevaporated to get crude product, which was purified by silica gel columnchromatography using 2% methanol in dichloromethane to afford the titlecompound5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.23 g, 40.3% yield) as off-white. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.31 (s, 1H), 8.60 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 7.69(s, 1H), 7.63 (d, J=8.4 Hz, 1H), 4.79 (s, 2H), 3.53 (t, J=6 Hz, 2H),3.30-3.26 (m, 2H), 1.94-1.91 (m, 2H), 1.79-1.76 (m, 2H). Calculated M+H:425.09; Found M+H: 425.1. HPLC purity: 98.55%.

Step 6:

Preparation of5-(4-chloro-3-(trifluoromethyl)phenyl)-7-(2-fluoroethyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

To a solution5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.08 g, 0.19 mmol) in acetone (15 mL) were added1-bromo-2-fluoro-ethane (0.07 mL, 0.95 mmol) followed by potassiumcarbonate (0.78 g, 0.57 mmol) at 0° C. and the reaction mixture washeated at 55° C. for 4 h. The reaction mixture was cooled, filtered andthe solid was washed with acetone. The combined filtrate wasconcentrated to get the crude product, which was purified by silica gelcolumn chromatography using 1.5% methanol in dichloromethane to affordthe title compound5-(4-chloro-3-(trifluoromethyl)phenyl)-7-(2-fluoroethyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.011 g, 12% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.56 (s, 1H), 8.19-8.16 (m, 2H), 7.83 (s, 1H), 7.68-7.66 (d, J=8.4 Hz,1H), 4.87-4.85 (m, 1H), 4.82 (s, 2H), 4.76-4.73 (m, 1H), 4.53-4.51 (m,1H), 4.46-4.45 (m, 1H), 3.55-3.51 (m, 2H), 3.31-3.27 (m, 2H), 1.95-1.90(m, 2H), 1.82-1.76 (m, 2H). Calculated M+H: 471.11; Found M+H: 471.0.HPLC purity: 95.02%.

TABLE 13 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 150

5-(4-chlorophenyl)-3- (2-oxo-2-(pyrrolidin- 1-yl)ethyl)-3H- pyrrolo[2,3-d]pyrimidin-4(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.15 (s, 1H),8.05 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 2.0 Hz, 1H), 7.34(d, J = 8.4 Hz, 2H), 4.76 (s, 2H), 3.54-3.50 (m, 2H), 3.31-3.27 (m, 2H),1.95-1.89 (m, 2H), 1.81-1.74 (m, 2H); Calculated (M + H): 357.10, Found(M + H): 357.1. HPLC purity: 98.65% 151

5-(4-chlorophenyl)-7- methyl-3-(2-oxo-2- (pyrrolidin-1- yl)ethyl)-3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.12 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.35 (d, J = 8.4Hz, 2H), 4.77 (s, 2H), 3.73 (s, 3H), 3.53-3.50 (m, 2H), 3.30-3.27 (m,2H), 1.94-1.89 (m, 2H), 1.81- 1.76 (m, 2H). Calculated (M + H): 371.12,Found (M + H): 371.3. HPLC purity: 99.39% 152

5-(4-chlorophenyl)-3- (2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-yl)ethyl)- 3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one 1H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.18 (s, 1H), 8.10-8.04 (m, 1H), 7.95-7.91(m, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 5.11-4.70(m, 3H), 3.73-3.60 (m, 2H), 2.17-1.91 (m, 4H); Calculated (M + H):425.09, Found (M + H): 425.0. HPLC purity: 97.51% 153

5-(4-chlorophenyl)-7- methyl-3-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-yl)ethyl)- 3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.17-8.14 (m, 1H), 8.91 (d, J = 8.0 Hz, 2H),7.55 (s, 1H), 7.36 (d, J = 7.6 Hz, 2H), 5.08-4.72 (m, 3H), 3.73 (s, 3H),3.70 (brs, 2H), 2.08-2.04 (m, 4H); Calculated (M + H): 439.11, Found(M + H): 439.1, HPLC purity: 98.23% 154

5-(4-chlorophenyl)-3- (2-(3,3- difluoroazetidin-1- yl)-2-oxoethyl)-3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.20 (s, 1H), 8.08 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 2.4Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 4.76 (t, J = 12.0 Hz, 2H), 4.69 (s,2H), 4.34 (t, J = 12.0 Hz, 2H); Calculated (M + H): 379.07, Found (M +H): 379.1. HPLC purity: 99.49% 155

5-(4-chlorophenyl)-3- (2-(3,3- difluoroazetidin-1- yl)-2-oxoethyl)-7-methyl-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 8.15 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 7.36 (d,J= 8.4 Hz, 2H), 4.75 (t, J = 12.4 Hz, 2H), 4.70 (s, 2H), 4.34 (t, J =12.4 Hz, 2H), 3.73 (s, 3H); Calculated (M + H): 393.09, Found (M + H):393.1. HPLC purity: 99.59% 156

5-(3-chloro-4- fluorophenyl)-3-(2- oxo-2-(pyrrolidin-1- yl)ethyl)-3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.19 (s, 1H), 8.29-8.27 (dd, J = 2 Hz, 7.2 Hz, 1H), 8.05 (s, 1H),7.92-7.89 (m, 1H), 7.55 (s, 1H), 7.33 (t, J = 9.2 Hz, 1H), 4.78 (s, 2H),3.53 (t, J = 6.8 Hz, 2H), 3.31- 3.27 (m, 2H), 1.97-1.90 (m, 2H),1.82-1.75 (m, 2H). Calculated (M + H): 375.09, Found (M + H): 375.1.HPLC purity: 99.72% 157

5-(4-chloro-3- (trifluoromethyl) phenyl)-7-ethyl-3-(2-oxo-2-(pyrrolidin-1- yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.57 (d, J = 1.6 Hz, 1H), 8.21-8.18(m, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.81 (s,2H), 4.18 (q, J = 7.2 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.29 (t, J =6.4 Hz, 2H), 1.97-1.90 (m, 2H), 1.81-1.75 (m, 2H), 1.39 (t, J = 7.2 Hz,3H). Calculated (M + H): 453.12, Found (M + H): 453.2. HPLC purity:99.25% 158

5-(4-chloro-3- (trifluoromethyl) phenyl)-7-methyl-3-(2-oxo-2-(pyrrolidin-1- yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.57 (d, J = 2.0 Hz, 1H), 8.18-8.15(m, 2H), 7.77 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 4.81 (s, 2H), 3.75 (s,3H), 3.534 (t, J = 6.4 Hz, 2H), 3.29 (t, J = 6.4 Hz, 2H), 1.95-1.90 (m,2H), 1.81-1.76 (m, 2H); Calculated (M + H): 439.11, Found (M + H):439.1. HPLC purity: 99.76% 159

5-(3-chloro-4- fluorophenyl)-7- methyl-3-(2-oxo-2- (pyrrolidin-1-yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one 1H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.27-8.25 (dd, J = 2.4 Hz, 7.6 Hz, 1H), 8.13 (s, 1H),7.88-7.84 (m, 1H), 7.62 (s, 1H), 7.37-7.32 (t, J = 9.2 Hz, 1 H), 4.79(s, 2H), 3.73 (s 3H), 3.54-3.51 (t, J = 7.2 Hz, 2H), 3.31-3.28 (t, J =7.6 Hz, 2H), 1.97-1.90 (m, 2H), 1.82-1.76 (m, 2H), Calculated (M + H):389.11, Found (M + H): 389.3. HPLC purity: 99.75% 160

5-(3-chloro-4- fluorophenyl)-7- ethyl-3-(2-oxo-2- (pyrrolidin-1-yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.27-8.25 (m, 1H), 8.12 (s, 1H), 7.91-7.88 (m, 1H),7.7 (s, 1H), 7.37-7.33 (t, J = 8.8 Hz, 1 H), 4.79 (s, 2H), 4.19-4.14 (q,J = 7.2 Hz, 2H), 3.54-3.51 (t, J = 6.8 Hz, 2H), 3.31-3.27 (t, J = 11.6Hz, 2H), 1.95-1.90 (m, 2H), 1.82-1.77 (m, 2H), 1.40-1.36 (t, J = 7.2 Hz,3H). Calculated (M + H): 403.13, Found (M + H): 403.4. HPLC purity:99.70% 161

5-(3-chloro-4- fluorophenyl)-3-(2- (3,3-difluoroazetidin-1-yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- onepyrrolo[2,3-d]pyrimidin-4(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.25 (s, 1H),8.28-8.26 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 8.08 (s, 1H), 7.91-7.89 (m, 1H),7.56 (s, 1H), 7.36-7.32 (t, J = 9.2 Hz, 1H), 4.8-4.71 (m, 4H), 4.38-4.32(t, J = 12.4 Hz, 2H); Calculated (M + H): 397.06, Found (M + H): 397.0.HPLC purity: 99.55% 162

5-(3-chloro-4- fluorophenyl)-3-(2- (3,3-difluoroazetidin-1-yl)-2-oxoethyl)-7- methyl-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.24 (d, J = 5.6 Hz, 1H), 8.14 (s, 1H),7.85 (s, 1H), 7.63 (s, 1H), 7.38-7.33 (t, J = 9.2 Hz, 1H), 4.79-4.73 (m,4H), 4.38-4.32 (t, J = 24.4 Hz, 2H), 3.73 (s, 3H); Calculated (M + H):411.08, Found (M + H): 411.0, HPLC purity: 99.13% 163

5-(3-chloro-4- fluorophenyl)-3-(2- (3,3-difluoroazetidin-1-yl)-2-oxoethyl)-7- ethyl-3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.26-8.24 (dd, J = 2 Hz, 7.6 Hz, 1H), 8.14(s, 1H), 7.90-7.87 (m, 1H), 7.71 (s, 1H), 7.38-7.34 (t, J = 9.2 Hz, 1H),4.80-4.73 (m, 4H), 4.35 (t, J = 12.4 Hz, 2H), 4.19-4.14 (m, 2H), 1.38(t, J = 7.6 Hz, 3H), Calculated (M + H): 425.09, Found (M + H): 425.0.HPLC purity: 98.83% 164

5-(4-chloro-3- fluorophenyl)-3-(2- oxo-2-(pyrrolidin-1- yl)ethyl)-3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.20 (s, 1H), 8.28 (dd, J = 2.0 Hz, 6.8 Hz, 1H), 8.06 (s, 1H),7.93-7.89 (m, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.33 (t, J = 8.8 Hz, 1H),4.78 (s, 2H), 3.53 (t, J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H), 2.04-1.90 (m, 2H), 1.82-1.75 (m, 2H); Calculated (M + H): 375.09, Found (M +H): 375.0. HPLC purity: 99.55% 165

5-(4-chloro-3- fluorophenyl)-7- methyl-3-(2-oxo-2- (pyrrolidin-1-yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.26 (dd, J = 2.4 Hz, 7.2 Hz, 1H), 8.13 (s, 1H),7.88-7.84 (m, 1H), 7.63 (s, 1H), 7.35 (t, J = 8.8 Hz, 1H), 4.80 (s, 2H),3.73 (s, 3H), 3.53 (t, J = 6.8 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H),1.95-1.90 (m, 2H), 1.82-1.76 (m, 2H); Calculated (M + H): 389.11, Found(M + H): 389.1, HPLC purity(%): 99.312. 166

5-(4-chloro-3- (trifluoromethyl) phenyl)-3-(2-(3,3- difluoroazetidin-1-yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.36 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.17 (d, J =8.4 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 4.77 (t, J = 12.0 Hz, 2H), 4.73 (s, 2H), 4.34 (t, J = 12.0 Hz,2H); Calculated (M + H): 447.06, Found (M + H): 447.0. HPLC purity:99.32% 167

5-(4-chloro-3- fluorophenyl)-3-(2- (3,3-difluoroazetidin-1-yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.25 (brs, 1H), 8.17 (dd, J = 1.6 Hz, 12.0 Hz,1H), 8.08 (s, 1H), 7.82 (dd, J = 2.0 Hz, 9.2 Hz, 1H), 7.64 (s, 1H), 7.47(t, J = 8.4 Hz, 1H), 4.77 (t, J = 12.0 Hz, 2H), 4.70 (s, 2H), 4.35 (t, J= 12.0 Hz, 2H); Calculated (M + H): 397.06, Found (M + H): 397.0. HPLCpurity: 98.90% 168

5-(4-chloro-3- (trifluoromethyl) phenyl)-3-(2-(3,3- difluoroazetidin-1-yl)-2-oxoethyl)-7- methyl-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.59 (s, 1H), 8.15 (d, J = 12.8 Hz, 2H),7.79 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 4.77 (t, J = 12.0 Hz, 2H), 4.74(s, 2H), 4.35 (t, J = 12.4 Hz, 2H), 3.75 (s, 3H); Calculated (M + H):461.07, Found (M + H): 461.0. HPLC purity: 99.48% 169

5-(4-chloro-3- (trifluoromethyl) phenyl)-3-(2-(3,3- difluoroazetidin-1-yl)-2-oxoethyl)-7- ethyl-3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.60 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 1.6Hz, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 4.77 (t,J = 12.0 Hz, 2H), 4.74 (s, 2H), 4.35 (t, J = 12.4 Hz, 2H), 4.18 (q, J =7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); Calculated (M + H): 475.09, Found(M + H): 475.0. HPLC purity: 98.79% 170

5-(4-chloro-3- fluorophenyl)-3-(2- (3,3-difluoroazetidin-1-yl)-2-oxoethyl)-7- methyl-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.16-8.12 (m, 2H), 7.76 (dd, J = 1.6 Hz,8.4 Hz, 1H), 7.71 (s, 1H), 7.51 (t, J = 8.4 Hz, 1H), 4.77 (t, J = 12.0Hz, 2H), 4.73 (s, 2H), 4.35 (t, J = 12.0 Hz, 2H), 3.73 (s, 3H);Calculated (M + H): 411.08, Found (M + H): 411.0. HPLC purity: 99.78%171

5-(4-chloro-3- fluorophenyl)-3-(2- (3,3-difluoroazetidin-1-yl)-2-oxoethyl)-7- ethyl-3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.15-8.13 (m, 2H), 7.79 (brs, 2H), 7.50 (t,J = 8.0 Hz, 1H), 4.80-4.72 (m, 4H), 4.35 (t, J = 12.0 Hz, 2H), 4.20-4.14(m, 2H), 1.38 (t, J = 7.2 Hz, 3H); Calculated (M + H): 425.09, Found(M + H): 425.0, HPLC purity(%): 98.557. 172

5-(3-chloro-4- fluorophenyl)-7-(2- fluoroethyl)-3-(2-oxo-2-(pyrrolidin-1- yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one 1HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.25 (d, J = 5.6 Hz, 1H), 8.14 (s , 1H),7.89-7.86 (m, 1H), 7.69 (s, 1H), 7.36 (t, J = 9.2 Hz, 1H), 4.85 (t, J =4.4 Hz, 1H), 4.80 (s, 2H), 4.73 (t, J = 4.4 Hz, 1H), 4.50 (t, J = 4.4Hz, 1H), 4.44 (t, J = 4.4 Hz, 1H), 3.53 (t, J = 6.4 Hz, 2H), 3.30 (t, J= 6.4 Hz, 2H), 1.95-1.90 (m, 2H), 1.82-1.77 (m, 2H). Calculated M + H:421.12; Found M + H: 421.0. HPLC purity: 98.11%. 173

5-(4-chloro-3- fluorophenyl)-7-(2- fluoroethyl)-3-(2-oxo-2-(pyrrolidin-1- yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.17-8.15 (m, 2H), 7.79- 7.77 (m, 2H),7.53-7.49 (m, 1H), 4.85 (t, J = 4.4 Hz, 1H), 4.80 (s, 2H), 4.74 (t, J =4.4 Hz, 1H), 4.52 (t, J = 4.4 Hz, 1H), 4.45 (t, J = 5.2 Hz, 1H), 3.53(t, J = 6.8 Hz, 2H), 3.30 (t, J = 7.2 Hz, 2H), 1.95-1.90 (m, 2H),1.82-1.77 (3, 2H). Calculated M + H: 421.12; Found M + H: 421.1, HPLC:99.92% 174

5-(4-fluoro-3- (trifluoromethyl) phenyl)-3-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.26 (s, 1H), 8.47 (d, J = 6.4 Hz, 1H), 8.22 (brs,1H), 8.08 (d, J = 2 Hz, 1H), 7.62 (s, 1H), 7.44 (t, J = 10 Hz, 1H),5.51-5.25 (m, 1H), 4.93-4.75 (m, 2H), 3.92-3.39 (m, 4H), 2.27-2.10 (m,2H). Calculated (M + H): 427.11, Found (M + H): 427.1, HPLC purity98.85%. 175

5-(3,4- dichlorophenyl)-3-(2- (3-fluoropyrrolidin-1- yl)-2-oxoethyl)-3H-pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.28 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.93(d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 5.51-5.26(m, 1H), 4.93-4.75 (m, 2H), 3.92-3.39 (m, 4H), 2.27-2.08 (m, 2H).Calculated (M + H): 409.06, Found (M + H): 409.0, HPLC purity 99.65%.176

5-(3-chloro-4- (trifluoromethyl) phenyl)-3-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.42 (s, 1H), 8.49 (s, 1H), 8.12-8.11 (m, 2H), 7.79(s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 5.51-5.26 (m, 1H), 4.94-4.77 (m, 2H),3.93- 3.40 (m, 4H), 2.27-2.10 (m, 2H). Calculated (M + H): 443.08, Found(M + H): 443.0, HPLC purity 99.25%. 177

5-(4-chloro-3- (trifluoromethyl) phenyl)-3-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.32 (s, 1H), 8.61 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H),8.10 (s, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 5.51-5.25 (m, 1H),4.94- 4.76 (m, 2H), 3.89-3.75 (m, 2H); 3.67-3.52 (m, 2H); 2.30-2.13 (m,2H); Calculated (M + H): 443.08, Found (M + H): 443.0, HPLC purity:99.18%. 178

5-(3-chloro-4- fluorophenyl)-3-(2- (3-fluoropyrrolidin-1-yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one 1H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.22 (s, 1H), 8.29-8.27 (dd, J = 2 Hz, 7.2 Hz, 1H),8.08 (d, J = 2.0 Hz, 1H), 7.912 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.33(t, J = 9.6 Hz, 1H), 5.51-5.25 (m, 1H), 4.92-4.78 (m, 2H), 3.89-3.79 (m,2H); 3.64- 3.42 (m, 2H); 2.30-2.10 (m, 2H); Calculated (M + H): 393.09,Found (M + H): 393.0, HPLC purity: 97.11%. 179

5-(4-Chloro-3-fluoro- phenyl)-3-[2-(3- fluoro-pyrrolidin-1-yl)-2-oxo-ethyl]-3,7- dihydro-pyrrolo[2,3- d]pyrimidin-4-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.20-8.17 (dd, J = 1.2 Hz, 12 Hz,1H), 8.09 (brs, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H),7.47 (t, J = 8 Hz, 1H), 5.51-5.26 (m, 1H), 4.91- 4.74 (m, 2H), 3.99-3.34(m, 4H), 2.29-1.93 (m, 2H). Calculated M + H: 393.09; Found M + H:393.4, HPLC purity: 98.36% 180

5-(5,6- dichloropyridin-3-yl)- 3-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)- one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.44 (s, 1H), 8.93 (d, J = 1.2 Hz, 1H), 8.86 (s, 1H),8.12 (s, 1H), 7.81 (s, 1H), 5.51-5.25 (t, J = 50.8 Hz, 1H), 4.94-4.76(m, 2H), 3.92-3.42 (m, 4H), 2.29-2.10 (m, 2H). Calculated (M + H):410.05, Found (M + H): 410.0, HPLC purity 99.35% 181

5-(4-Chloro-3- trifluoromethyl- phenyl)-3-[2- ((3R,4S)-3,4-difluoro-pyrrolidin-1-yl)-2- oxo-ethyl]-3,7- dihydro-pyrrolo[2,3-d]pyrimidin-4-one- d]pyrimidin-4-one 1H NMR (400 MHz, DMSO-d₆) δ (ppm):12.34 (s, 1H), 8.61 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H),7.70 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 5.24-5.48 (m, 2H), 4.89- 4.80(m, 2H), 4.06-3.48 (m, 4H). Calculated M + H: 461.07; Found M + H:461.1. HPLC purity: 96.10%. 182

5-(6-chloro-5- (trifluoromethyl) pyridin-3-yl)-3-(2-(3,3-difluoroazetidin-1- yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.52 (s, 1H), 9.18 (s, 1H), 9.10(s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 4.81-4.74 (m, 4H), 4.35 (t, J =11.2 Hz, 2H). Calculated M + H: 448.05; Found M + H: 448.1, HPLC purity:97.97% 183

5-(6-chloro-5- (trifluoromethyl) pyridin-3-yl)-3-(2-(3-fluoropyrrolidin-1- yl)-2-oxoethyl)-3H- pyrrolo[2,3- d]pyrimidin-4(7H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.47 (s, 1H), 9.18 (s, 1H), 9.09(s, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 5.51-5.25 (m, 1H), 4.96-4.82 (m,2H), 3.84-3.58 (m, 4H), 2.30- 2.13 (m, 2H). Calculated M + H: 444.08;Found M + H: 444.1, HPLC: 99.87% 184

1-Ethyl-5-[2-(3- fluoro-pyrrolidin-1- yl)-2-oxo-ethyl]-3-(4- fluoro-3-trifluoromethyl- phenyl)-1,5-dihydro- pyrrolo[3,2-c]pyridin- 4-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.44 (d, J = 6 Hz, 1H), 8.22 (brs, 1H),8.15 (s, 1H), 7.77 (s, 1H), 7.45 (t, J = 10 Hz, 1H), 5.51-5.25 (m, 1H),4.94-4.76 (m, 2H), 4.19- 4.15 (m, 2H), 3.92-3.26 (m, 4H), 2.30-1.95 (m,2H), 1.39 (t, J = 7.6 Hz, 3H). Calculated M + H: 455.14; Found M + H:455.1. HPLC: 99.50%

Example 185: Preparation of5-(4-chloro-3-(trifluoromethyl)phenyl)-7-(2-methoxyethyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

To a solution5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.08 g, 0.19 mmol) in N,N-dimethylformamide (10 mL), sodium hydride(0.018 g, 0.38 mmol) was added at 0° C. and the reaction mixture wasstirred at room temperature for 30 minutes. Then1-bromo-2-methoxy-ethane (0.068 mL, 0.57 mmol) was added at 0° C. andthe reaction mixture was stirred at room temperature for 4 h. Thereaction mixture was quenched with cold water (20 mL) and stirred for 30minutes to get precipitation. The precipitated solid was filtered,washed with pentane and dried under vacuum. The crude product waspurified by silica gel column chromatography using 1.5% methanol indichloromethane to afford the title compound5-(4-chloro-3-(trifluoromethyl)phenyl)-7-(2-methoxyethyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.028 g, 30% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.56 (s, 1H), 8.18-8.14 (m, 2H), 7.79 (s, 1H), 7.66 (d, J=8.4 Hz, 1H),4.81 (s, 2H), 4.32 (brs, 2H), 3.75-3.71 (m, 2H), 3.53 (t, J=6.8 Hz 2H),3.31-3.27 (m, 2H), 3.23 (s, 3H), 1.93 (t, J=6.8 Hz, 2H), 1.78 (t, J=6.8Hz, 2H). Calculated M+H: 483.13; Found M+H: 483.3. HPLC: 97.24%.

TABLE 14 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 186

5-(3-chloro-4- fluorophenyl)-7-(2- methoxyethyl)-3-(2-oxo-2-(pyrrolidin-1- yl)ethyl)-3H- pyrrolo[2,3-d]pyrimidin- 4(7H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.27-8.24 (dd, J = 2 Hz, 7.2 Hz, 1H),8.12 (s, 1H), 7.89- 7.85 (m, 1H), 7.64 (s, 1H), 7.35 (t, J = 9.6 Hz,1H), 4.79 (s, 2H), 4.30 (t, J = 5.2 Hz, 2H), 3.73- 3.69 (m, 2H), 3.53(t, J = 6.4 Hz, 2H), 3.31-3.21 (m, 5H), 1.97- 1.90, ( m, 2H), 1.82-1.76(m, 2H). Calculated M + H: 433.14; Found M + H: 433.3. HPLC: 97.92% 187

5-(4-chloro-3- fluorophenyl)-7-(2- methoxyethyl)-3-(2-oxo-2-(pyrrolidin-1- yl)ethyl)-3H- pyrrolo[2,3-dlpyrimidin- 4(7H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.18 (s, 1H), 8.14 (m, 1H), 7.78 (d, J =8.4 Hz, 1H), 7.72 (s, 1H), 7.50 (t, J = 8.4 Hz, 1H), 4.79 (s, 2H), 4.30(t, J = 4.8 Hz, 2 H), 3.70 (t, J = 5.2 Hz, 2H), 3.53 (t, J = 6.8 Hz,2H), 3.31-3.23 (m, 5H), 1.93 (t, J = 6.8 Hz, 2H), 1.82-1.77 (m, 2H).Calculated M + H: 433.14; Found M + H: 433.1, HPLC: 99.97% 188

5-(4-fluoro-3- (trifluoromethyl)phenyl)- 3-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-7-(2- methoxyethyl)-3H-pyrrolo[2,3-d]pyrimidin- 4(7H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.42 (d, J = 6 Hz, 1H), 8.20 (brs, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.45(t, J = 10 Hz, 1H), 5.51-5.25 (m, 1H), 4.94-4.80 (m, 2H), 4.31 (t, J =5.2 Hz, 2H), 3.89-3.27 (m, 6H), 3.237 (s, 3H), 2.30-2.10 (m, 2H).Calculated M + H: 485.15; Found M + H: 485.1. HPLC: 99.27% 189

5-(4-fluoro-3- (trifluoromethyl)phenyl)- 3-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-7- (methoxymethyl)-3H-pyrrolo[2,3-d]pyrimidin- 4(7H)-one ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.04-7.99 (m, 2H), 7.96 (d, J = 3.2 Hz, 1H), 7.19 (t, J = 9.6 Hz, 1H),7.15 (s, 1H), 5.52 (s, 2H), 5.45-5.2 (m, 1H), 5.02-4.92 (m, 1H),4.54-4.44 (m, 1H), 4.0- 3.5 (m, 4H), 3.35 (s, 3H), 2.45- 1.9 (m, 2H).Calculated M + H: 471.14; Found M + H: 471.3. HPLC: 99.38%

Example 190: Preparation of5-(4-chloro-3-(trifluoromethyl)phenyl)-7-cyclopropyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

To a solution of5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.08 g, 0.188 mmol) in dichloromethane (10 mL), triethylamine (0.13 mL,0.943 mmol) and copper(II)acetate mono hydrate (0.112 g, 0.565 mmol)were added and the reaction mixture was stirred at room temperature for16 h under air. Then the reaction mixture heated at 45° C. for 3 h. Thereaction mixture was quenched with cold water (20 mL) and extracted withdichloromethane (3×30 mL). The combined organic layer was dried overanhydrous sodium sulphate, filtered and concentrated. The crude compoundwas purified by silica gel column chromatography using 1% methanol indichloromethane to afford5-(4-chloro-3-(trifluoromethyl)phenyl)-7-cyclopropyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.011 g, 12.8% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.57 (s, 1H), 8.21 (d, J=8 Hz, 1H), 8.15 (s, 1H), 7.72 (s, 1H),7.64 (d, J=8.4 Hz, 1H), 4.81 (s, 2H), 3.63-3.62 (m, 1H), 3.53 (t, J=6.8Hz, 2H), 1.93 (t, J=6.4 Hz, 2H), 1.78 (t, J=6.8 Hz, 2H), 1.09-1.03 (m,4H); 2H are merged in DMSO water. Calculated M+H: 465.12; Found M+H:465.0. HPLC purity: 98.22%.

TABLE 15 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 191

5-(4-chloro-3- fluorophenyl)-7- cyclopropyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)- 3H-pyrrolo[2,3- d]pyrimidin-4(7H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.16 (d, J = 11.6 Hz, 2H), 7.84 (d, J = 8.4Hz, 1H), 7.65 (s, 1H), 7.48 (t, J = 8.4 Hz, 1H), 4.80 (s, 2H), 3.62 (d,J = 4 Hz, 1H), 3.53 (t, J = 6.4 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H), 1.93(t, 6.8 Hz, 2H), 1.78 (t, J = 6.8 Hz, 2H), 1.07-1.02 (m, 4H). CalculatedM + H: 415.13; Found M + H: 415.1. HPLC purity: 99.7% 192

5-(3-chloro-4- fluorophenyl)-7- cyclopropyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)- 3H-pyrrolo[2,3- d]pyrimidin-4(7H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.25 (d, J = 5.6 Hz, 1H), 8.13 (s, 1H),7.94-7.91 (m , 1H), 7.57 (s, 1H), 7.33 (t, J = 8.8 Hz, 1H), 4.80 (s,2H), 3.63-3.58 (m, 1H), 3.53 (t, J = 6.4 Hz, 2H), 3.29 (t, J = 6.8 Hz,2H), 1.95- 1.90 (m, 2H), 1.82-1.75 (m, 2H), 1.07-1.00 (m, 4H).Calculated M + H: 415.13; Found M + H: 415.1. HPLC: 99.20% 193

7-cyclopropyl-5-(4- fluoro-3- (trifluoromethyl)phenyl)- 3-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-3H- pyrrolo[2,3-d]pyrimidin-4(7H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.43 (d, J = 5.6 Hz, 1H),8.23 (brs, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.64 (s, 1H), 7.44 (t, J = 10Hz, 1H), 5.51-5.25 (m, 1H), 4.94-4.76 (m, 2H), 3.927- 3.31 (m, 5H),2.30-1.952 (m, 2H), 1.21-1.01 (m, 4H), Calculated M + H: 467.14; FoundM + H: 467.1. HPLC purity: 99.76%

Example 194: Preparation of5-(4-chloro-3-(trifluoromethyl)phenyl)-7-(2-hydroxyethyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

Step-1:

Preparation of7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

To a solution5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.07 g, 0.166 mmol) in N,N-dimethylformamide mL), sodium hydride (0.018g, 0.332 mmol) was added at 0° C. Then the reaction mixture was stirredat room temperature for 30 minutes. Then(2-Bromo-ethoxy)-tert-butyl-dimethyl-silane (0.119 g, 0.498 mmol) wasadded at 0° C. and the reaction mixture was stirred at room temperaturefor 3 h. The reaction mixture was quenched with cold water (20 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layer wasdried over anhydrous sodium sulphate, filtered and concentrated toafford the title compound7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.221 g, crude) as gummy liquid. The crude product was as such takenfor next step without further purification.

Step-2:

Preparation of5-(4-chloro-3-(trifluoromethyl)phenyl)-7-(2-hydroxyethyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

To a solution7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.220 g, 0.377 mmol) in tetrahydrofuran (30 mL), tetra butyl ammoniumfluoride (0.32 mL, 1.13 mmol) was added at 0° C. and the solution wasstirred at room temperature for 2 h. The reaction mixture was quenchedwith cold water (20 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated. The crude compound was purified bypreparative HPLC (column: chemsil C18 (250 mm×4.6 mm×50, mobile phase(A): 0.01% ammonia in water, mobile phase (B): acetonitrile, flow rate:1.0 mL/min, T/% B: 0/20, 5/80, 25/90, 27/20, 30/20, wavelength: 254 nm)to afford the title compound5-(4-chloro-3-(trifluoromethyl)phenyl)-7-(2-hydroxyethyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one(0.020 g, 2.8% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.57 (s, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.13 (s, 1H), 7.78 (s, 1H), 7.65(d, J=8.4 Hz, 1H), 4.95 (s, 1H), 4.81 (s, 2H), 4.20 (s, 2H), 3.76-3.74(m, 2H), 3.53 (t, J=6.8 Hz, 2H), 1.93 (t, J=6.8 Hz, 2H), 1.78 (t, J=6.8Hz, 2H). 2H are merged in DMSO water peak. Calculated M+H: 469.12; FoundM+H: 469.2. HPLC purity: 99.87%.

TABLE 16 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 195

5-(3-chloro-4- fluorophenyl)-7- (2- hydroxyethyl)-3- (2-oxo-2-(pyrrolidin-1- yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin- 4(7H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.26 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H),7.873 (brs, 1H), 7.63 (s, 1H), 7.35 (t, J = 8.8 Hz, 1H), 4.94 (s, 1H),4.79 (s, 2H), 4.18 (bs, 2H), 3.74 (d, J = 4.4 Hz, 2H), 3.53 (t, J = 6Hz, 2H), 3.29-3.27 (m, 2H), 1.93 (t, J = 6.4 Hz, 2H), 1.78 (t, J = 6.4Hz, 2H). Calculated M + H: 419.12; Found M + H: 419.1. HPLC purity:99.94% 196

5-(4-fluoro-3- (trifluoromethyl) phenyl)-3-(2-(3- fluoropyrrolidin-1-yl)-2- oxoethyl)-7-(2- hydroxyethyl)- 3H-pyrrolo[2,3- d]pyrimidin-4(7H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.43 (d, J = 6.8 Hz, 1H),8.20 (brs, 1H), 8.14 (s, 1H), 7.70 (s, 1H), 7.45 (t, J = 9.6 Hz, 1H),5.51-5.25 (m, 1H), 4.96-4.77 (m, 3H), 4.21-4.19 (t, J = 5.2 Hz, 2H),3.89-3.31(m, 6H), 2.30- 1.95 (m, 2H), Calculated M + H: 471.14; FoundM + H: 471.3. HPLC purity: 99.58% 197

5-(4-chloro-3- fluorophenyl)-7- (2- hydroxyethyl)-3- (2-oxo-2-(pyrrolidin-1- yl)ethyl)-3H- pyrrolo[2,3- d]pyrimidin- 4(7H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.18-8.13 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H),7.71(s, 1H), 7.49 (t, J = 8.4 Hz, 1H), 4.95 (s, 1H), 4.79 (s, 2H), 4.19(t, d = 5.2 Hz, 2H), 3.74 (d, J = 4 Hz, 2H), 3.53 (t, J = 6.8 Hz, 2H),3.29 (m, 2H), 1.93 (t, J = 6.8 Hz, 2H), 1.78 (t, J = 6.8 Hz, 2H).Calculated M + H: 419.12; Found M + H: 419.2, HPLC purity: 99.85%

C. Preparation of Pyrrolopyridones Example 198: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

Step 1:

Preparation of1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde

To a stirred suspension of sodium hydride (60% dispersion in mineraloil) (9.16 g, 228.70 mmol) in tetrahydrofuran was added a solution of1H-pyrrole-2-carbaldehyde (14.5 g, 152.47 mmol) in tetrahydrofuran at 0°C. and stirred for 30 min. Then, (2-(chloromethoxy)ethyl)trimethylsilane(SEMCl) (40.6 mL, 228.70 mmol) was added at 0° C. portion wise (15 mintime interval) and stirred at room temperature for 2 h. After completionof reaction (monitored by TLC), mixture was quenched with ice cold water(100 mL), extracted with ethyl acetate (3×500 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered and evaporatedunder vacuum to afford crude product, which was purified by silica gel(60-120) column chromatography using 5% ethyl acetate in hexane toafford title compound1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde (25.9 g,75.5% yield) as a yellow liquid. Calculated (M+H): 226.12, Found (M+H):226.1.

Step 2:

Preparation of4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde

To a solution of14(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde (25.9 g,114.93 mmol) in tetrahydrofuran (200 mL) was added N-bromosuccinimide(21.5 g, 120.80 mmol) at −20° C. and stirred at 0° C. for 2 h. Aftercompletion of reaction, the reaction mixture was poured on to hexane(200 mL), solid suspension was filtered off, the filtrate wasconcentrated under vacuum to afford crude product, which was purified bysilica gel (60-120) column chromatography using 10% ethyl acetate inhexane to afford title compound4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde(26.33 g, crude) as a yellow liquid. Calculated (M+H): 304.03, Found(M+H): 304.0.

Step 3:

Preparation of(E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylicacid

To a mixture of4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde(26.33 g, 86.54 mmol) and malonic acid (10.81 g, 103.84 mmol) inpyridine (50 mL), was added morpholine (0.73 g, 8.65 mmol) at roomtemperature and stirred at 120° C. for 18 h. After completion ofreaction, the reaction mixture was cooled to room temperature andconcentrated under vacuum to afford crude product, which was purified bysilica gel (60-120) column chromatography using 30% ethyl acetate inhexane to afford title compound(E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylicacid (18.0 g, 60.2% Yield) as brown solid. Calculated (M+H): 346.04;Found (M+H): 346.0.

Step 4:

Preparation of(E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acryloylazide

To a stirred solution of(E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylicacid (18.0 g, 51.98 mmol) in N,N-dimethylformamide (30 mL), was addedtriethylamine (7.98 mL, 57.18 mmol) and diphenylphosphorylazide (12.32mL, 57.18 mmol) at 0° C. and stirred at room temperature for 4 h. Aftercompletion of reaction mixture, the mixture was poured on to 500 mL ofice cold water, extracted with ethyl acetate (2×500 mL). The combinedorganic layer was concentrated under vacuum to afford title compound(E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acryloylazide (24.0 g, crude) as brown liquid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):7.64 (d, J=15.6 Hz, 1H), 6.89 (s, 1H), 6.72 (s, 1H), 6.19-6.14 (m, 1H),5.24 (s, 2H), 3.48 (t, J=8.0 Hz, 2H), 1.25 (s, 1H), 0.88 (t, J=8.0 Hz,2H), −0.022 (s, 9H).

Step 5:

Preparation of3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred solution of(E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acryloylazide (24.0 g, 64.64 mmol) in diphenyl ether (50 mL), was addedtributylamine (16.9 mL, 71.10 mmol) at room temperature and stirred at100° C. for 10 min, the temperature was raised to 160° C. and stirredfor 16 h. After completion of the reaction, mixture was allowed to coolto room temperature and loaded to silica gel (60-120) column directly.Initially the column was eluted with hexane to remove diphenyl ether,then eluted with 5% methanol in dichloromethane to afford3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(6.0 g, 27% yield) as brown solid. Calculated (M+H): 343.04, Found(M+H): 343.0.

Step 6:

Preparation of ethyl ethyl2-(3-bromo-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)acetate

To a stirred suspension of3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(6.0 g, 17.48 mmol) in acetone (200 mL), was added potassium carbonate(7.24 g, 52.43 mmol) and ethyl 2-bromoacetate (3.88 mL, 34.96 mmol) atroom temperature, stirred at 55° C. for 2 h. After completion ofreaction, the reaction mixture cooled to room temperature, filtered andwashed with acetone. The filtrate was concentrated under vacuum toafford crude product, which was purified by silica gel columnchromatography using 50% ethyl acetate in hexane to afford ethyl2-(3-bromo-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)acetate(4.7 g, 62.8% yield) as brown solid. Calculated (M+H): 429.08, Found(M+H): 429.10.

Step 7:

Preparation of2-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid

To a stirred suspension of ethyl2-(3-bromo-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)acetate(2.0 g, 4.66 mmol) in a mixture of 1,4-dioxane:water (50 mL, 4:1) wasadded (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (1.57 g, 6.99mmol) at room temperature and the resulting mixture was purged withnitrogen for 10 min. To the above mixture was added[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (0.19 g, 0.23 mmol) and potassium carbonate(1.93 g, 13.97 mmol) under nitrogen, the reaction mixture was stirred at110° C. for 16 h. After completion of reaction, the mixture was cooledto room temperature, diluted with water (30 mL), acidified with 2Nhydrochloric acid and extracted with ethyl acetate (3×500 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford crude product, whichwas purified by silica gel column chromatography using 15% methanol indichloromethane to afford2-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid (2.26 g, crude) as brown solid. Calculated (M+H): 501.11, Found(M+H): 501.10.

Step 8:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To the stirred suspension of2-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid (0.25 g, 0.50 mmol) and pyrrolidine (0.071 g, 1.02 mmol) indichloromethane (10 mL), was added triethylamine (0.3 g, 3.08 mmol). Thereaction mixture was cooled to 0° C., was added 1-propylphosphonicanhydride (50% solution in ethyl acetate) (0.44 mL, 0.75 mmol), andstirred at room temperature for 4 h. The reaction mixture was dilutedwith dichloromethane (50 mL), washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford crude product, which was purified by silica gel columnchromatography using 5% methanol in dichloromethane to afford titlecompound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.1 g, crude). Calculated (M+H): 554.18, Found (M+H): 554.1.

Step 9:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.1 g, 0.18 mmol) in triethylsilane (0.058 mL, 0.36 mmol), was addedtrifluoroacetic acid (0.55 mL, 7.21 mmol) at room temperature andstirred for 1 h. After completion of reaction, reaction mixture wasevaporated under vacuum and the residue was diluted with 1 mL ofacetonitrile and 3 mL of ammonium hydroxide. The resulting mixture wasstirred for 2 h at room temperature, and acidified with 2N hydrochloricacid at 0° C. The precipitated product was filtered and dried to affordthe crude product, which was purified by preparative HPLC method(column: chemsil, C18 (250 mm×4.6 mm×50, mobile phase (A): 0.01% ammoniain water, mobile phase (B): acetonitrile, flow rate: 1.0 mL/min, T/% B:0/20, 10/80, 25/80, 27/20, 30/20, at 254 nm) to afford title compound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.02 g, 26.3% yield) as off white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 11.90 (brs, 1H), 8.49 (d, J=1.6 Hz, 1H), 8.11 (dd, J=1.6 Hz,J=8.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.21 (d, J=7.2 Hz,1H), 6.44 (d, J=7.6 Hz, 1H), 4.72 (s, 2H), 3.52-3.49 (m, 2H), 3.29-3.26(m, 2H), 1.95-1.88 (m, 2H), 1.80-1.73 (m, 2H). Calculated (M+H): 424.10,Found (M+H): 424.0, HPLC purity: 99.79%.

TABLE 17 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 199

3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.40 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H),5.47-5.24 (m, 3H), 4.84-4.72 (m, 2H) 3.81-3.49 (m, 6H), 2.32-1.95 (m,2H), 0.83 (t, J = 8.0 Hz, 2H), −0.073 (s, 9H). Calculated (M + H):572.17, Found (M + H): 572.3, HPLC purity: 99.70% 200

3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-(3,3-difluoroazetidin-1-yl)-2- oxoethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.45 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H),7.65 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 7.6 Hz,1H), 5.47 (s, 2H), 4.72 (t, J = 12.0 Hz, 2H), 4.66 (s, 2H), 4.31 (t, J =12.0 Hz, 2H), 3.51 (t, J = 8.0 Hz, 2H), 0.83 (t, J = 8.0 Hz, 2H), −0.080(s, 9H); Calculated (M + H): 576.14, Found (M + H): 576.0, HPLC purity:99.90% 201

3-(4-chloro-3- fluorophenyl)-5-(2-oxo- 2-(pyrrolidin-1- yl)ethyl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[3,2- c]pyridin-4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.07 (d, J = 12.0 Hz, 1H), 7.69-7.67(m, 2H), 7.48 (t, J = 8.4 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 6.64 (d, J= 7.6 Hz, 1H), 5.46 (s, 2H), 4.72 (s, 2H), 3.53-3.49 (m, 4H), 3.30-3.27(m, 2H), 1.95-1.88 (m, 2H), 1.80-1.74 (m, 2H), 0.83 (t, J = 8.0 Hz, 2H),−0.075 (s, 9H); Calculated (M + H): 504.18, Found (M + H): 504.5, HPLCpurity: 99.69% 202

3-(4-chloro-3- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.06 (d, J = 12.0Hz, 1H), 7.68 (m, 2H), 7.48 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 7.2 Hz,1H), 6.65 (d, J = 7.2 Hz, 1H), 5.49-5.24 (m, 3H), 4.86- 4.72 (m, 2H),3.86-3.32 (m, 6H), 2.30-2.09 (m, 2H), 0.83 (t, J = 12.0 Hz, 2H), −0.07(s, 9H); Calculated (M + H): 522.17, Found (M + H): 522.1, HPLC purity:99.72% 203

3-(4-chloro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 11.80 (s, 1H), 8.48 (s, 1H), 8.11 (d,J = 8.0 Hz, 1H), 7.60 (m 2H), 7.24 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 7.2Hz, 1H), 5.49-5.24 (m, 1H), 4.86- 4.71 (m, 2H), 3.90-3.36 (m, 4H),2.30-1.93 (m, 2H). Calculated (M + H): 442.09, Found (M + H): 442.0,HPLC purity: 96.92% 204

3-(4-chloro-3- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz)δ (ppm): 11.75 (s, 1H), 8.13- 8.10 (m, 1H), 7.73 (d, J = 8.4 Hz, 1H),7.53 (s, 1H), 7.44 (t, J = 8.4 Hz, 1Hz), 7.24 (d, J = 7.2 Hz, 1H), 6.43(d, J = 7.6 Hz, 1H), 5.49-5.24 (m, 1H), 4.84- 4.68 (m, 2H), 3.89-3.37(m, 4H), 2.47-1.96 (m, 2H); Calculated (M + H): 392.09, Found (M + H):392.0, HPLC purity: 98.62% 205

3-(3-chloro-4- fluorophenyl)-5-(2-oxo- 2-(pyrrolidin-1- yl)ethyl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[3,2- c]pyridin-4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.13 (dd, J = 1.6 Hz, J = 5.2 Hz,1H), 7.78-7.75 (m, 1H), 7.61 (s, 1H), 7.36-7.31 (m, 2H), 6.63 (d, J =7.2 Hz, 1H), 5.45 (s, 2H), 4.72 (s, 2H), 3.53- 3.49 (m, 4H), 3.39-3.27(m, 2H), 1.93-1.90 (m, 2H), 1.80- 1.77 (m, 2H), 0.83 (t, 8.0 Hz, 2H),0.10 (s, 9H). Calculated (M + H): 504.18, found (M + H): 504.1, HPLCpurity: 99.2% 206

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.13 (dd, J = 1.6Hz, J = 6.0 Hz, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.36-7.32 (m, 2H), 6.64(d, J = 7.6 Hz, 1H), 5.49- 5.24 (m, 3H), 4.86-4.71 (m, 2H), 3.86-3.37(m, 6H), 2.25- 2.08 (m, 2H), 0.83 (t, J = 8.0 Hz, 2H), 0.10 (s, 9H).Calculated (M + H): 522.17, found (M + H): 522.5, HPLC purity: 98.91%207

3-(3-chloro-4- fluorophenyl)-5-(2-(3,3- difluoroazetidin-1-yl)-2-oxoethyl)-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 8.12 (d, J = 6.4Hz, 1H), 7.76 (s, 1H), 7.61 (s, 1H), 7.36-7.32 (m, 2H), 6.67 (d, J = 7.2Hz, 1H), 5.45 (s, 2H), 4.71- 4.65 (m, 4H), 4.32 (s, 2H), 3.50 (t, J =7.6 Hz, 2H), 082 (t, J = 8.0 Hz, 2H), 0.001 (s, 9H). Calculated (M + H):526.15, found (M + H): 526.2, HPLC purity: 98.47% 208

3-(3-chloro-4- fluorophenyl)-5-(2-oxo- 2-(pyrrolidin-1- yl)ethyl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm):11.67 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.80 (s, 1H), 7.44 (s, 1H),7.30 (t, J = 9.2 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.41 (d, J = 7.6 Hz,1H), 4.71 (s, 2H), 3.50 (t, J = 6.8 Hz, 2H), 3.28 (d, J = 11.6 Hz, 2H),1.92 (t, J = 6.4 Hz, 2H), 1.77 (d, J = 6.4 Hz, 2H). Calculated (M + H):374.10, found (M + H): 374.4, HPLC purity: 98.20% 209

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz)δ (ppm): 11.69 (s, 1H), 8.17 (t, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.45 (s,1H), 7.30 (t, J = 8.8 Hz, 1H), 7.22 (d, J = 6.8 Hz, 1H), 6.42 (d, J =7.2 Hz, 1H), 5.49- 5.24 (m, 1H), 4.85-4.70 (m, 2H), 3.86-3.79 (m, 1H),3.77- 3.66 (m, 2H), 3.62-3.50 (m, 1H), 2.30-2.22 (m, 1H), 2.11- 2.08 (m,1H). Calculated (M + H): 392.09, found (M + H): 392.0, HPLC purity:98.05% 210

3-(5,6-dichloropyridin- 3-yl)-5-(2-(3,4- difluoropyrrolidin-1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400MHz) δ (ppm): 11.93 (s, 1H), 8.82 (d, J = 7.2 Hz, 2H), 7.71 (s, 1H),7.26 (d, J = 7.2 Hz, 1H), 6.47 (d, J = 7.2 Hz, 1H), 5.5-5.2 (m, 2H),4.84-4.76 (m, 2H), 4.08- 4.01 (m, 1H), 3.78-3.69 (m, 2H), 3.66-3.63 (m,1H). Calculated (M + H): 428.23, Found (M + H): 427.2. HPLC purity:99.66%

Example 211: Preparation of3-(4-chloro-3-fluorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

Step 1:

Preparation of2-(3-(4-chloro-3-fluorophenyl)-4-oxo-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid

To a stirred suspension of2-(3-(4-chloro-3-fluorophenyl)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid (0.1 g, 0.22 mmol) in triethylsilane (0.12 mL, 0.44 mmol), wasadded trifluoro acetic acid (0.85 mL, 11.10 mmol) at room temperatureand stirred for 1 h. After completion of reaction, reaction mixture wasevaporated under vacuum and the residue was diluted with 1 mL ofacetonitrile and 3 mL of ammonium hydroxide. The resulting mixture wasstirred for 2 h at room temperature, and acidified with 2N hydrochloricacid at 0° C. The precipitated product was filtered and dried to affordthe title compound2-(3-(4-chloro-3-fluorophenyl)-4-oxo-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid (0.05 g, 70.4% yield) as off white solid. Calculated (M+H): 321.04,Found (M+H): 321.0.

Step 2:

Preparation of3-(4-chloro-3-fluorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To the stirred suspension of22-(3-(4-chloro-3-fluorophenyl)-4-oxo-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid (0.05 g, 0.15 mmol) and pyrrolidine (0.022 g, 0.31 mmol) indichloromethane (10 mL), was added triethylamine (0.1 g, 0.94 mmol). Thereaction mixture was cooled to 0° C., was added 1-propylphosphonicanhydride (50% solution in ethyl acetate) (0.074 g, 0.23 mmol), andstirred at room temperature for 4 h. The reaction mixture was dilutedwith dichloromethane (25 mL), washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford crude product, which was purified by silica gel (60-120) columnchromatography using 5% methanol in dichloromethane to afford titlecompound3-(4-chloro-3-fluorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.02 g, 34.5% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 11.73 (s, 1H),8.13 (d, J=12.0 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.48 (t,J=8.4 Hz, 1H), 7.22 (d, J=6.8 Hz, 1H), 6.42 (d, J=7.6 Hz, 1H), 4.71 (s,2H), 3.52-3.49 (m, 2H), 3.30-3.27 (m, 2H), 1.94-1.89 (m, 2H), 1.80-1.75(m, 2H). Calculated (M+H): 374.10, found (M+H): 374.1, HPLC purity:98.55%.

TABLE 18 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 212

3-(4-chloro-3- (trifluoromethyl) phenyl)-5-(2-(3,3-difluoroazetidin-1-yl)- 2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 11.84 (s, 1H), 8.53 (s, 1H), 8.08 (d,J = 8.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 6.8 Hz, 1H),6.47 (d, J = 6.8 Hz, 1H), 4.73 (t, J = 11.6 Hz, 2H), 4.64 (s, 2H), 4.31(t, J = 11.6 Hz, 2H). Calculated (M + H): 446.06, found (M + H): 446.0,HPLC purity: 98.52%. 213

3-(4-chloro-3- fluorophenyl)-5-(2- (3,3-difluoroazetidin-1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 11.78 (s, 1H), 8.11 (d, J = 11.2 Hz, 1H), 7.72 (d, J =8.4 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.25(d, J = 6.8 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 4.41 (t, J = 11.6 Hz,2H), 4.63 (s, 2H), 4.32 (t, J = 12.0 Hz, 2H), Calculated (M + H):396.06, found (M + H): 396.0, HPLC purity: 98.29% 214

3-(3,4-dichlorophenyl)- 5-(2-(3- fluoropyrrolidin-1-yl)- 2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm):11.75 (s, 1H), 8.30 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.53-7.49 (m,2H), 7.24 (d, J = 7.2 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 5.49-5.24 (m,1H), 4.85-4.70 (m, 2H), 3.89-3.81 (m, 1H), 3.77-3.66 (m, 2H), 3.62-3.50(m, 1H), 2.30-2.22 (m, 1H), 2.11-2.08 (m, 1H); Calculated (M + H):408.06, found (M + H): 408.0, HPLC purity: 99.68% 215

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one1H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 11.74 (s, 1H), 8.34 (d, J = 7.2 Hz,1H), 8.12 (brs, 1H), 7.50 (s, 1H), 7.41 (t, J = 9.6 Hz, 1H), 7.23 (d, J= 7.2 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 5.49- 5.24 (m, 1H), 4.84-4.68(m, 2H), 3.89-3.36 (m, 4H), 2.30- 1.92 (m, 2H). Calculated (M + H):426.12, found (M + H): 426.2, HPLC purity: 98.13% 216

5-(2-(3,3- difluoroazetidin-1-yl)- 2-oxoethyl)-3-(4- fluoro-3-(trifluoromethyl) phenyl)-1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 11.78 (s, 1H), 7.38 (d, J = 6.4 Hz, 1H),8.11 (brs, 1H), 7.53 (s, 1H), 7.41 (t, J = 9.6 Hz, 1H), 7.25 (d, J = 7.2Hz, 1H), 6.46 (d, J = 7.2 Hz, 1H), 4.72 (t, J = 12.0 Hz, 2H), 4.63 (s,2H), 4.31 (t, J = 12.0 Hz, 2H). Calculated (M + H): 430.09, found (M +H): 430.2, HPLC purity: 99.46% 217

3-(3,4-dichlorophenyl)- 5-(2-oxo-2-(pyrrolidin- 1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm):11.74 (s, 1H), 8.30 (s, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.52-7.49 (m,2H), 7.22 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 4.71 (s, 2H),3.50 (t, J = 6.4 Hz, 2H), 3.26 (s, 2H), 1.92 (t, J = 6.4 Hz, 2H), 1.77(t, J = 6.4 Hz, 2H). Calculated (M + H): 390.07, found (M + H): 390.1,HPLC purity: 99.30% 218

3-(3-chloro-4- fluorophenyl)-5-(2- (3,3-difluoroazetidin-1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 11.73 (s, 1H), 8.18 (dd, J = 2.0 Hz, J = 5.6 Hz, 1H),7.80-7.78 (m, 1H), 7.47 (s, 1H), 7.31 (t, J = 9.2 Hz, 1H), 7.24 (d, J =7.6 Hz, 1H), 6.45 (d, J = 6.8 Hz, 1H), 4.71 (s, 2H), 4.64 (s, 2H), 4.32(s, 2H); Calculated (M + H): 396.06, found (M + H): 396.1, HPLC purity:98.01% 219

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)- 1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 11.72 (s, 1H), 8.34 (d, J = 6.0 Hz, 1H),8.12 (t, J = 5.6 Hz, 1H), 7.50 (s, 1H), 7.41 (t, J = 6.0 Hz, 1H), 7.21(d, J = 7.2 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 4.71 (s, 2H), 3.52-3.48(m, 2H), 3.29-3.27 (m, 2H), 1.94- 1.88 (m, 2H), 1.80-1.73 (m, 2H).Calculated (M + H): 408.13, found (M + H): 408.1, HPLC purity: 99.35%220

5-(2-(3,4- difluoropyrrolidin-1- yl)-2-oxoethyl)-3-(4- fluoro-3-(trifluoromethyl) phenyl)-1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 11.7 (s, 1H), 8.34 (d, J = 6.4 Hz, 1H), 8.13(brs, 1H), 7.51 (s, 1H), 7.41 (t, J = 9.2 Hz, 1H), 7.22 (d, J = 7.2 Hz,1H), 6.44 (d, J = 7.6 Hz, 1H), 5.46- 5.23 (m, 2H), 4.82-4.71 (m, 2H),4.08-3.27 (m, 4H). Calculated (M + H): 444.11, Found (M + H): 444.2,HPLC purity: 99.28% 221

3-(6-chloro-5- (trifluoromethyl) pyridin-3-yl)-5-(2-(3,4-difluoropyrrolidin-1- yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 11.97 (s, 1H), 9.08 (s,1H), 9.02 (s, 1H), 7.78 (s, 1H), 7.27 (d, J = 6.8 Hz, 1H), 6.49 (d, J =6.8 Hz, 1H), 5.47-5.23 (m, 2H), 4.85-4.73 (m, 2H), 4.08-4.00 (m, 1H),3.82-3.63 (m, 2H), 3.62-3.27 (m, 1H); Calculated (M + H): 461.07, Found(M + H): 461.0, HPLC purity: 99.2% 222

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 11.76 (s, 1H), 8.38 (d, J = 5.6 Hz,1H), 8.12-8.1 (m, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.42 (t, J = 9.2 Hz,1H), 7.25 (d, J = 7.2 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 4.57 (s, 2H),4.44-4.28 (m, 2H), 3.98-3.93 (m, 2H), 1.58 (d, J = 22 Hz, 3H).Calculated (M + H): 426.12, Found (M + H): 426.3, HPLC purity: 96.35%223

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3- methylazetidin-1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz)δ (ppm): 11.72 (brs, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.81-7.79 (m, 1H),7.64 (s, 1H), 7.31 (t, J = 9.2 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H), 6.44(d, J = 7.6 Hz, 1H), 4.58 (s, 2H), 4.39-4.27 (m, 2H), 3.98-3.94 (m, 2H),1.59 (d, J = 22.4 Hz, 3H). Calculated (M − H): 392.09, found (M − H):392.3, HPLC purity: 99.97%

Example 224: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

In a seal tube, a stirred suspension of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.075 g, 0.17 mmol) in toluene (2 mL), was added 2-bromopyridine (0.032mL, 0.34 mmol), N,N-dimethylethylenediamine (0.037 mL, 0.34 mmol) andpotassium phosphate tribasic monohydrate (0.117 g, 0.51 mmol) at roomtemperature and resulting mixture was purged with argon for 15 min. Thencopper(I)iodide was added at room temperature and stirred at 110° C. for16 h. The reaction mixture was cooled to room temperature, diluted withdichloromethane (10 mL), filtered and washed with ethyl acetate (20 mL),the filtrate was concentrated under vacuum to afford the crude product,which was purified by silica gel (60-120) column chromatography using 2%methanol in dichloromethane to afford title compound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.05 g, 56.8% yield) as off-white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.61 (d, J=3.2 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.15 (d, J=7.6Hz, 2H), 8.09-8.04 (m, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz,1H), 7.46-7.40 (m, 2H), 7.26 (d, J=7.2 Hz, 1H), 5.50-5.25 (m, 1H),4.92-4.74 (m, 2H), 3.91-3.32 (m, 4H), 2.30-1.93 (m, 2H). Calculated(M+H): 519.11, found (M+H): 519.1, HPLC purity: 99.62%

TABLE 19 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 225

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1-(pyridin-2- yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.60 (d, J = 4.0Hz, 1H), 8.30 (d, J = 6.4 Hz, 1H), 8.18 (brs, 1H), 8.10 (s, 1H), 8.06(t, J = 8.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.51-7.39 (m, 3H), 7.26(d, J = 7.6 Hz, 1H), 5.50-5.24 (m, 1H), 4.91-4.74 (m, 2H), 3.90- 3.82(m, 1H), 3.80-3.66 (m, 2H), 3.66-3.57 (m, 1H), 2.30- 2.22 (m, 1H),2.09-2.07 (m, 1H). Calculated (M + H): 503.14, Found (M + H): 503.1,HPLC purity: 99.32% 226

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1-(pyridin-3- yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.88 (s, 1H),8.69 (s, 1H), 8.33 (d, J = 6.4 Hz, 1H), 8.19 (s, 1H), 8.09 (d, J = 7.6Hz, 1H), 7.91 (s, 1H), 7.65 (t, J = 4.4 Hz, 1H), 7.48 (t, J = 10 Hz,1H), 7.39 (d, J = 7.2 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 5.50-5.24 (m,1H), 4.92-4.76 (m, 2H), 3.87- 3.80 (m, 1H), 3.63-3.50 (m, 2H), 3.40-3.26(m, 1H), 2.25- 2.22 (m, 1H), 2.12-2.09 (m, 1H); Calculated (M + H):503.14, Found (M + H): 503.1, HPLC purity: 99.74% 227

3-(4-chloro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1-(pyridin-3- yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 8.88 (d, J = 1.6Hz, 1H), 8.69 (d, J = 4.4 Hz, 1H), 8.45 (s, 1H), 8.17 (d, J = 8.4 Hz,1H), 8.10 (d, J = 7.6 Hz, 1H), 7.98 (s, 1H), 7.70- 7.64 (m, 2H), 7.40(d, J = 7.2 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 5.50-2.25 (m, 1H), 4.93-4.75 (m, 2H), 3.91-3.38 (m, 4H), 2.26-1.94 (m, 2H). Calculated (M + H):519.11; Found (M + H): 519.1. HPLC Purity: 97.6% 228

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(pyridin-2- yl)-1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H NMR(400 MHz, DMSO- d₆) δ (ppm): 8.62 (brs, 1H), 7.89 (t, J = 7.6 Hz, 1H),7.79 (d, J = 7.2 Hz, 1H), 7.68 (brs, 1H), 7.45 (brs, 2H), 7.31-7.13 (m,4H), 5.41-5.27 (m, 1H), 5.18-5.03 (m, 1H), 4.55-4.41 (m, 1H), 3.96- 3.84(m, 2H), 3.74-3.53 (m, 2H), 2.38-1.94 (m, 2H). Calculated (M + H):469.12; Found (M + H): 469.1. HPLC Purity: 99.82% 229

3-(3,4-dichlorophenyl)- 5-(2-(3-fluoropyrrolidin- 1-yl)-2-oxoethyl)-1-(pyridin-2-yl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400MHz) δ (ppm): 8.60 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.11(s, 1H), 8.06 (t, J = 7.2 Hz, 1H), 7.90-7.84 (m, 2H), 7.59 (d, J = 8.4Hz, 1H), 7.45-7.40 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 5.50-5.25 (m, 1H),4.92-4.74 (m, 2H), 3.91-3.3 (m, 4H), 2.26-2.08 (m, 2H); Calculated (M +H): 485.09, Found (M + H): 485.1, HPLC purity: 99.7%

Example 230: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.12 g, 0.28 mmol) in dichloromethane (5 mL), triethylamine (0.08 mL,0.56 mmol) and copper(II)acetate mono hydrate (0.084 g, 0.42 mmol) wereadded and the reaction mixture was purged with air for 10 min. Thenphenyl boronic acid (0.051 g, 0.42 mmol) was added and the reactionmixture was stirred at room temperature for 16 h and then at 45° C. for3 h in the presence of air. The reaction mixture was diluted withdichloromethane, washed with water, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford the crude product,which was purified by silica gel column chromatography using 5% methanolin dichloromethane. Again it was purified by preparative HPLC (Column:Chemsil C18(250 mm×4.6 mm×5μ), mobile phase (A): 0.01% ammonia in water,mobile phase (B): acetonitrile, flow rate: 1.0 mL/min, T/% B: 0/20,12/80, 25/80, 27/20, 30/20 at 220 nm) to afford3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-phenyl-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.035 g, 25% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm):8.34 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.83 (s, 1H), 7.61-7.58 (m, 4H),7.49-7.44 (m, 2H), 7.35 (d, J=5.6 Hz, 1H), 6.48 (d, J=7.6 Hz, 1H),5.50-5.24 (m, 1H), 4.91-4.74 (m, 2H), 3.90-3.80 (m, 3H), 3.72-3.32 (m,1H), 2.47-2.12 (m, 1H), 2.09-2.04 (m, 1H). Calculated (M+H): 502.15,Found (M+H): 502.1, HPLC purity 99.9%.

TABLE 20 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 231

1-cyclopropyl-3-(4- fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.30 (d, J = 6.4 Hz, 1H), 8.13 (s,1H), 7.52 (s, 1H), 7.41 (t, J = 9.6 Hz, 1H), 7.34 (d, J = 6.8 Hz, 1H),6.65 (d, J = 7.6 Hz, 1H), 5.49-5.24 (m, 1H), 4.87-4.72 (m, 2H),3.86-3.40 (m, 5H), 2.30-1.96 (m, 2H), 1.04-1.01 (m, 4H). Calculated (M +H): 466.15, Found (M + H): 466.1. HPLC purity: 99.57% 232

3-(3-chloro-4- fluorophenyl)-1- cyclopropyl-5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.15 (d, J = 7.6 Hz, 1H), 7.81 (s,1H), 7.46 (s, 1H), 7.35-7.28 (m, 2H), 6.63 (d, J = 6.8 Hz, 1H),5.49-5.25 (m, 1H), 4.87-4.72 (m, 2H), 3.89-3.28 (m, 5H), 2.3-2.08 (m,2H), 1.01 (d, J = 12.4 Hz, 4H). Calculated (M + H): 432.12, Found (M +H): 432.1, HPLC purity: 98.69% 233

1-cyclopropyl-3-(3,4- dichlorophenyl)-5-(2- (3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 8.26 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H),7.54 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 6.65(d, J = 7.2 Hz, 1H), 5.50-5.24 (m, 1H), 4.87- 4.70 (m, 2H), 3.9-3.55 (m,5H), 2.30-1.96 (m, 2H), 1.08- 0.98 (m, 4H); Calculated (M + H): 448.09,Found (M + H): 448.4, HPLC purity: 99.9% 234

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)-1-(1- methyl-1H-1,2,4-triazol-3-yl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400MHz) δ (ppm): 8.31 (d, J = 6.4 Hz, 1H), 8.25 (s, 1H), 8.16 (brs, 1H),7.84 (s, 1H), 7.72 (s, 1H), 7.46 (t, J = 9.6 Hz, 1H), 7.37 (d, J = 6.8Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 5.5-5.25 (m, 1H), 4.91-4.75 (m, 2H),3.91 (s, 3H), 3.88-3.27 (m, 4H), 2.31-2.08 (m, 2H). Calculated (M + H):506.15, Found (M + H): 506.1, HPLC purity: 99.57% 235

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1- methyl-1H-pyrazol-4- yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.25 (s, 1H),8.17 (d, J = 7.2 Hz, 1H), 7.84 (brs, 2H), 7.67 (s, 1H), 7.38- 7.29 (m,2H), 6.51 (d, J = 6.8 Hz, 1H), 5.51-5.25 (m, 1H), 4.9-4.75 (m, 2H), 3.91(s, 3H), 3.87-3.31 (m, 4H), 2.31-2.1 (m, 2H). Calculated (M + H):472.13, Found (M + H): 472.1, HPLC purity: 97.09% 236

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoro-3-methylazetidin- 1-yl)-2- oxoethyl)-1-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.35(d, J = 6 Hz, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 7.73 (s,1H), 7.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 4.62 (s, 2H), 4.41- 4.29 (m,2H), 3.99-3.91 (m, 5H) 1.59 (d, J = 22 Hz, 3H). Calculated (M + H):406.45, Found (M + H): 406.1, HPLC purity: 96.11% 237

3-(3-chloro-4- fluorophenyl)-1- cyclopropyl-5-(2-(3-ethyl-3-fluoroazetidin- 1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.16 (d, J = 7.2 Hz 1H),7.83-7.79 (m, 1H), 7.47 (s, 1H), 7.36-7.29 (m, 2H), 6.65 (d, J = 7.2 Hz,1H), 4.6 (s, 2H), 4.37-4.29 (m, 2H), 3.99-3.9 (m, 2H), 3.48-3.47 (m,1H), 1.92-1.84 (m, 2H), 1.08-1.01 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H).Calculated (M + H): 446.14, Found (M + H): 446.0, HPLC purity: 97.32%

Example 238: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(methoxymethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.1 g, 0.24 mmol) in N,N-dimethylformamide (2 mL), was added sodiumhydride (60% dispersion in oil)(0.019 g, 0.47 mmol), at 0° C. andstirred at room temperature for 20 min. The reaction mixture was cooledto 0° C. and was added bromo(methoxy)methane (0.058 g, 0.47 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature andstirred for 2 h. The reaction mixture was quenched with cold water (20mL), the precipitated product was filtered, washed thoroughly withwater, dried to afford crude product which was purified by preparativeHPLC (column: chemsil C18(250 mm×4.6 mm×5μ), mobile phase (A): 0.01%ammonia in water, mobile phase (B): acetonitrile, flow rate: 1.0 mL/min,T/% B: 0/20, 10/80, 25/80, 27/20, 30/20 at 254 nm) to afford3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(methoxymethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.07 g, 25% yield) as white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm):8.28 (d, J=7.2 Hz, 1H), 8.12 (s, 1H), 7.68 (s, 1H), 7.44 (t, J=10.0 Hz,1H), 7.35 (d, J=7.2 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 5.45-5.23 (m, 3H),4.88-4.72 (m, 2H), 3.81-3.79 (m, 1H), 3.62-3.42 (m, 3H), 3.23 (s, 3H),2.37-2.12 (m, 1H), 2.09-2.04 (m, 1H). Calculated (M+H): 470.14, Found(M+H): 470.1, HPLC purity: 99.05%

TABLE 21 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 239

1-ethyl-3-(4-fluoro-3- (trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin- 1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.29 (d, J = 5.6 Hz, 1H),8.12 (brs, 1H), 7.59 (s, 1H), 7.44-7.39 (m, 1H), 7.30 (d, J = 7.2 Hz,1H), 6.62 (d, J = 7.2 Hz, 1H), 5.49- 5.24 (m, 1H), 4.86-4.69 (m, 2H),4.15-4.10 (m, 2H), 3.86- 3.37 (m, 4H), 2.30-1.96 (m, 2H), 1.36 (t, J =7.6 Hz, 3H). Calculated (M + H): 454.15, Found (M + H): 454.2, HPLCpurity: 99.70%. 240

1-(2-(dimethylamino) ethyl)-3-(4-fluoro-3- (trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin- 1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.27 (d, J = 6.8 Hz, 1H),8.11 (brs, 1H), 7.58 (s, 1H), 7.43 (t, J = 9.6 Hz, 1H), 7.29 (d, J = 7.2Hz, 1H), 6.63 (d, J = 7.2 Hz, 1H), 5.5-5.25 (m, 1H), 4.8-4.73 (m, 2H),4.16-4.15 (m, 2H), 3.9- 3.5 (m, 4H), 2.61 (t, J = 6.4 Hz, 2H), 2.23-2(s, 8H). Calculated (M + H): 497.19, Found (M + H): 497.0, HPLC purity:98.73% 241

1-(ethoxymethyl)-3-(4- fluoro-3- (trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin- 1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.28 (d, J = 6.4 Hz, 1H),8.13 (brs, 1H), 7.68 (s, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.35 (d, J = 7.2Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.48-5.25 (m, 3H), 4.88-4.69 (m, 2H),3.9-3.27 (m, 6H), 2.31-2.07 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H).Calculated (M + H): 484.16, Found (M + H): 484.0. HPLC purity: 99.68%242

5-(2-(3,4- difluoropyrrolidin-1-yl)- 2-oxoethyl)-3-(4-fluoro-3-(trifluoromethyl) phenyl)- 1-(methoxymethyl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.29(d, J = 6.4 Hz, 1H), 8.12 (brs, 1H), 7.69 (s, 1H), 7.45 (t, J = 9.2 Hz,1H), 7.34 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 5.45-5.24 (m,4H), 4.84-4.73 (m, 2H), 4.08-3.44 (m, 4H), 3.23 (s, 3H). Calculated (M +H): 488.13, Found (M + H): 488.1. HPLC purity: 99.74% 243

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1- (pyrimidin-2-yl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.92 (d, J = 4.8 Hz, 2H),8.28 (s, 1H), 8.23 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.72 (d, J = 7.6Hz, 1H), 7.50-7.45 (m, 3H), 5.50- 5.25 (m, 1H), 4.93-4.76 (m, 2H),3.91-3.41 (m, 4H), 2.30- 1.93 (m, 2H). Calculated (M + H): 504.14, Found(M + H): 504.10. HPLC purity: 99.61% 244

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1- (pyrimidin-4-yl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 9.18 (s, 1H), 8.95 (d, J =5.6, 1H), 8.28 (s, 2H), 8.17 (s, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 6.4 Hz, 2H), 5.50-5.25 (m, 1H), 4.93-4.75 (m, 2H), 4.03-3.72 (m, 2H), 3.69-3.27 (m, 2H), 2.20- 1.96 (m, 2H);Calculated (M + H): 504.14, Found (M + H): 504.1, HPLC purity: 98.50%245

3-(3-chloro-4- fluorophenyl)-1-(2- (dimethylamino)ethyl)-5-(2-(3-fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.14 (d, J = 6 Hz, 1H),7.78 (bs, 1H), 7.52 (s, 1H), 7.34-7.27 (m, 2H), 6.61 (d, J = 7.2 Hz,1H), 5- 5.25 (m, 1H), 4.82-4.73 (m, 2H), 4.15 (t, J = 6.4 Hz, 2H),3.79-3.57 (m, 4H), 2.61 (t, J = 6 Hz, 2H), 2.22-2.12 (s, 8H). Calculated(M + H): 463.16, Found (M + H): 463.1, HPLC purity: 99.2% 246

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1- (methoxymethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.15-8.13 (m, 1H), 7.78 (brs, 1H), 7.62 (s,1H), 7.36-7.32 (m, 2H), 6.66 (d, J = 7.6 Hz, 1H), 5.5-5.25 (m, 3H),4.87-4.73 (m, 2H), 3.81-3.4 (m, 4H), 3.23 (s, 3H), 2.31-2.09 (m, 2H).Calculated (M + H): 436.12, Found (M + H): 436.1, HPLC purity: 98.18%247

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-methyl-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 8.12 (dd, J = 2 Hz, 7.6 Hz, 1H), 7.77 (brs, 1H), 7.46(s, 1H), 7.43-7.3 (m, 2H), 6.57 (d, J = 7.2 Hz, 1H), 5.5-5.25 (m, 1H),4.82- 4.74 (m, 2H), 3.9.3.75 (m, 2H), 3.73 (s, 3H), 3.63-3.3 (m, 2H),2.38-2.01 (m, 2H). Calculated (M + H): 406.11, Found (M + H): 406.1,HPLC purity: 92.56% 248

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(pyrimidin- 4-yl)-1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR(400 MHz, DMSO- d₆) 6 (ppm): 9.17 (s, 1H), 8.95 (d, J = 5.6 Hz, 1H),8.22 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 6 Hz, 1H), 7.85(brs, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.41 (t,J = 8.8 Hz, 1H), 5.72-5.25 (m, 1H), 4.92- 4.75 (m, 2H), 3.9-3.22 (m,4H), 2.30-1.94 (m, 2H), Calculated (M + H): 470.1, Found (M + H): 470.1,HPLC purity: 98.05% 249

3-(3,4-dichlorophenyl)-5- (2-(3-fluoropyrrolidin-1- yl)-2-oxoethyl)-1-(methoxymethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 8.24 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H),7.55 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 6.8 Hz,1H), 5.50-5.25 (m, 3H), 4.88-4.73 (m, 2H), 3.87-3.41 (m, 4H), 3.27 (s,3H), 2.26-1.97 (m, 2H); Calculated (M + H): 452.09, Found (M + H):452.1, HPLC purity: 100% 250

3-(3,4-dichlorophenyl)-5- (2-(3-fluoropyrrolidin-1- yl)-2-oxoethyl)-1-methyl-1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.26 (d, J = 1.6 Hz, 1H), 7.8 (d, J = 8.4 Hz, 1H), 7.55-7.51 (m,2H), 7.32 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 5.38- 5.25 (m,1H), 4.87-4.72 (m, 2H), 3.86-3.73 (m, 4H), 3.63- 3.32 (m, 3H), 2.30-2.12(m, 2H); Calculated (M + H): 422.08, Found (M + H): 422.1. HPLC purity:98.2% 251

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1- methyl-1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.30 (d, J = 6 Hz, 1H), 8.11 (brs, 1H), 7.53(s, 1H), 7.43 (t, J = 9.2 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 6.59 (d, J= 7.6 Hz, 1H), 5.5- 5.25 (m, 1H), 4.83-4.74 (m, 2H), 3.81-3.33 (m, 7H),2.38- 2.01 (m, 2H). Calculated (M + H): 440.13, Found (M + H): 440.1,HPLC purity: 99.47% 252

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 1-(2-fluoroethyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.27 (d, J = 6.4 Hz, 1H), 8.11 (s,1H), 7.58 (s, 1H), 7.44 (t, J = 9.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H),6.65 (d, J = 7.2 Hz, 1H), 5.54-5.31 (m, 1H), 4.88-4.45 (m, 4H),4.42-4.50 (m, 2H), 3.91-3.4 (m, 4H), 2.31-1.99 (m, 2H). Calculated (M +H): 472.14, Found (M + H): 472.1, HPLC purity: 99.87% 253

3-(3-chloro-4- fluorophenyl)-1-(2- fluoroethyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.13 (dd, J = 2.0 Hz, 7.6 Hz, 1H),7.74- 7.82 (m, 1H), 7.52 (s, 1H), 7.36-7.30 (m, 2H), 6.63 (d, J = 7.6Hz, 1H), 5.38 (t, J = 49.2 Hz, 1H), 4.87-4.71 (m, 4H), 4.48-4.40 (m,2H), 3.90- 3.48 (m, 4H), 2.30-1.90 (m, 2H). Calculated (M + H): 438.11,found (M + H): 438.1, HPLC purity: 98.20% 254

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-1- (methoxymethyl)-1,5- dihydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.16-8.14 (m, 1H),7.80-7.76 (m, 1H), 7.63 (s, 1H), 7.37 (m, 2H), 6.68 (d, J = 7.6 Hz, 1H),5.43 (s, 2H), 4.60 (s, 2H), 4.40-4.28 (m, 2H), 4.02-3.94 (m, 2H), 3.22(s, 3H), 1.59 (d, J = 21.6 Hz, 3H). Calculated (M + H): 436.12; Found(M + 1): 436.1. HPLC purity 99.63%

Example 255: Preparation of2-(3-(3-chloro-4-fluorophenyl)-4-oxo-M-pyrrolo[3,2-c]pyridin-5(4H)-yl)acetamide

To a stirred suspension of5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.08 g, 0.143 mmol) in triethylsilane (0.1 mL, 0.429 mmol), was addedtrifluoroacetic acid (2 mL) at room temperature and stirred for 1 h.After completion of reaction, reaction mixture was evaporated undervacuum and the residue was diluted with 2 mL of acetonitrile and 25 mLof ammonium hydroxide. The resulting mixture was stirred for 24 h atroom temperature, and acidified with 2N hydrochloric acid at 0° C. Theprecipitated product was filtered and dried to afford the title compound2-(3-(3-chloro-4-fluorophenyl)-4-oxo-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)acetamide(0.03 g, 25% yield) as an off white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 11.66 (s, 1H), 8.21 (d, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.46-7.44(m, 2H), 7.30 (1, J=8.8 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.02 (s, 1H),6.39 (d, J=6.8 Hz, 1H), 4.49 (s, 2H). Calculated (M+H): 320.05, Found(M+H): 320.1, HPLC purity: 99.61%.

Example 256: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

Step-1:

To a stirred solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2-((trimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.2 g, 0.47 mmol) in N,N-dimethylformamide (10 mL) was added sodiumhydride (60% dispersion in mineral oil) (0.04 g, 0.94 mmol) at 0° C. andstirred for 30 min. To the above mixture (2-bromoethoxy) trimethylsilane(0.4 ml, 1.41 mmol) was added at 0° C. and stirred at room temperaturefor 3 h. After completion of the reaction (monitored by TLC), themixture was quenched with ice cold water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layer were dried overanhydrous sodium sulfate filtered and concentrated to afford crudeproduct, which was purified by silica gel (60-120) column chromatographyusing 5% methanol in dichloromethane to afford title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2-((trimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.2 g crude) as brown color semi solid. (The crude was taken as such tonext step).

Step 2:

To a stirred suspension of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2-((trimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.2 g, 0.34 mmol) in tetrahydrofuran (5 mL), was addedtetrabutylammoniumfluoride solution (2 mL, 1.0 M in THF), and thereaction mixture was refluxed for 3 h. After completion of reaction, thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (2×100 mL), the combined organic layer were dried over anhydroussodium sulfate, filtered, concentrated under vacuum to afford the crudeproduct. The crude product was purified by preparative HPLC (Column:Chemsil C18(250 mm×4.6 mm×50, mobile phase (A): 0.01% ammonia in water,mobile phase (B): methanol, flow rate: 1.0 mL/min T/% B: 0/20, 10/80,25/80, 27/20, 30/20) to afford a title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.019 g, 11.87% yield) as a white solid. H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.28 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 8.10 (brs, 1H), 7.52 (s, 1H),7.44-7.39 (m, 1H), 7.29-7.27 (m, 1H), 6.61 (d, J=7.2 Hz, 1H), 5.49-5.24(m, 1H), 4.92-4.69 (m, 3H), 4.14-4.12 (m, 2H), 3.90-3.31 (m, 6H),2.30-1.93 (m, 2H). Calculated (M+H): 470.14, Found (M+H): 470.1, HPLCpurity 98.28%.

Example 257: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.05 g, 0.11 mmol) in acetonitrile (3 mL), 2,2-dimethyloxirane andcesium carbonate (0.06 g, 0.17 mmol) were added. The reaction mixturewas heated in a sealed tube at 95° C. for 16 h. After completion of thereaction, the reaction mixture was quenched with water (20 mL) andextracted with dichloromethane (3×50 mL). The combined organic layer waswashed with brine solution, dried over anhydrous sodium sulfate,filtered and evaporated to afford the crude product which was purifiedby silica gel column chromatography using 20% ethyl acetate indichloromethane to afford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.032 g, 55.2% yield) as off-white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.26 (d, J=6 Hz, 1H), 8.08 (brs, 1H), 7.45-7.4 (m, 2H), 7.26 (d,J=7.2 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 5.5-5.2 (m, 1H), 4.82-4.69 (m,3H), 3.99 (s, 2H), 3.82-3.57 (m, 4H), 2.3-2 (m, 2H), 1.11 (s, 6H).Calculated (M+H): 498.17, Found (M+H): 498.0. HPLC purity: 98.44%.

TABLE 22 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 258

5-(2-(3,4- difluoropyrrolidin-1- yl)-2-oxoethyl)-3-(4- fluoro-3-(trifluoromethyl)phenyl)- 1-(2-hydroxy-2- methylpropyl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.27(d, J = 6.8 Hz, 1H), 8.08 (brs, 1H), 7.45- 7.4 (m, 2H), 7.25 (d, J = 7.6Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 5.5-5.2 (m, 2H), 4.82- 4.69 (m, 3H),4.05-3.47 (m, 6H), 1.1 (s, 6H). Calculated (M + H): 516.16, Found (M +H): 516.3, HPLC purity: 99.47% 259

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2- hydroxy-2- methylpropyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.12 (d, J = 6.8 Hz, 1H),7.75 (brs, 1H), 7.39 (s, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.25 (d, J = 6.8Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5- 5.25 (m, 1H), 4.81-4.68 (m, 3H),3.98 (s, 2H), 3.79-3.57 (m, 4H), 2.31-2.0 (m, 2H), 1.1 (s, 6H).Calculated (M + H): 464.15, Found (M + H): 464.1, HPLC purity: 97.9%

Example 260: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(hydroxymethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.15 g, 0.27 mmol) in triethylsilane (0.086 mL, 0.54 mmol),trifluoroacetic acid (1.0 mL, 13.51 mmol) was added at room temperatureand the reaction mixture was stirred at the same temperature for 20 min.After completion of reaction, the reaction mixture was evaporated undervacuum, the residue was diluted with water (50 mL) and extracted withdichloromethane (2×50 mL). The combined organic layer was dried overanhydrous sodium sulphate, filtered and concentrated. The crude productwas purified by prep HPLC (kinetex C18 (100 mm×4.6 mm×2.6 μm), mobilephase (A): 0.01% TFA in water, mobile phase (B): acetonitrile, flowrate: 0.75 ml/min) to afford title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(hydroxymethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.071 g, 57.72% yield) as off white solid. 1H-NMR (DMSO-d6, 400 MHz) δ(ppm): 8.28 (d, J=6.4 Hz, 1H), 8.09 (brs, 1H), 7.58 (s, 1H), 7.43 (t,J=10 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 6.80-6.60 (m, 2H), 5.49-5.25 (m,3H), 4.87-4.7 (m, 2H), 3.9-3.25 (m, 4H), 2.31-2.07 (m, 2H). Calculated(M+H): 456.13, Found (M+H): 456.1, HPLC purity: 99.97%.

Example 261: Preparation of3-(3-chloro-4-fluorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.1 g, 0.25 mmol) in N,N-dimethylformamide (5 mL), oxetan-3-yl4-methylbenzenesulfonate (0.14 g, 0.64 mmol) and cesium carbonate (0.25g, 0.77 mmol) were added. The reaction mixture was heated at 100° C. for48 h. After completion of the reaction, the reaction mixture wasquenched with water (20 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layer was washed with brine solution (50 mL), driedover anhydrous sodium sulfate, filtered and evaporated to afford thecrude product which was purified by silica gel column chromatographyusing 2% methanol in dichloromethane to afford the title compound3-(3-chloro-4-fluorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.0055 g, 5% yield) as pale yellow solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.19 (dd, J=2 Hz, 7.2 Hz, 1H), 7.95 (s, 1H), 7.9-7.87 (m, 1H),7.37-7.32 (m, 2H), 6.62 (d, J=7.2 Hz, 1H), 5.69-5.65 (m, 1H), 5.49-5.25(m, 1H), 4.99-4.71 (m, 6H), 3.89-3.32 (m, 4H), 2.31-1.94 (m, 2H).Calculated (M+H): 448.12, Found (M+H): 448.1, HPLC purity: 97.34%.

TABLE 23 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 262

3-(4-fluoro-3- (trifluoromethyl) phenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1- (pyridazin-4-yl)-1H- pyrrolo[3,2- c]pyridin-4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 9.7 (s, 1H), 9.4 (d, J = 6 Hz, 1H),8.3 (d, J = 6.4 Hz, 1H), 8.19 (brs, 1H), 8.08-8.04 (m, 2H), 7.55-7.48(m, 2H), 6.82 (d, J = 7.6 Hz, 1H), 5.51-5.25 (m, 1H), 4.94- 4.76 (m,2H), 3.91-3.58 (m, 4H), 2.13-1.97 (m, 2H). Calculated (M + H): 504.14,Found (M + H): 504.1, HPLC purity: 99.21%

Example 263: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[3,2-e]pyridin-4(5H)-one

Step-1:

Preparation ofN′-acetyl-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carbohydrazide

Triethylamine (0.08 mL, 0.587 mmol) and phosgene (0.17 mL, 0.353 mmol)were added sequentially to an ice cold solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.1 g, 0.235 mmol) in tetrahydrofuran (10 mL) and the reaction mixturewas stirred at 0° C. for 20 minutes. Then acetohydrazide (0.02 g, 0.28mmol) in tetrahydrofuran (3 mL) was added and stirring was continued for1 h at room temperature. The reaction mixture was quenched with coldwater (20 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated to afford the crude product which was purified by silica gelcolumn chromatography using 8% methanol in dichloromethane to afford thetitle compoundN-acetyl-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carbohydrazide(0.04 g, 32% yield) as a white solid. Calculated (M+H): 526.1, Found(M+H): 526.1.

Step-2:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a solution ofN′-acetyl-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carbohydrazide(0.04 g, 0.076 mmol) in toluene (5 mL) was added phosphorus oxychloride(0.007 mL, 0.0761 mmol) and the reaction mixture was stirred at 110° C.for 2 h. The reaction mixture was quenched with cold water (20 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and evaporated to affordthe crude product which was purified by silica gel column chromatographyusing 4% methanol in dichloromethane to afford3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.004 g, 10% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 8.27 (d, J=6.4 Hz, 1H), 8.15 (brs, 1H), 8.01 (s, 1H), 7.61 (d,J=6.8 Hz, 1H), 7.50 (t, J=9.6 Hz, 1H), 7.21 (d, =7.2 Hz, 1H), 5.38-5.25(m, 1H), 4.94-4.81 (m, 2H), 3.82-3.26 (m, 4H), 2.58 (s, 3H), 2.3-2.0 (m,2H). Calculated (M+H): 508.1, Found (M+H): 508.1, HPLC purity: 97.56%.

TABLE 24 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 264

3-(3-chloro-4- fluorophenyl)-5-(2- (3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(5- methyl-1,3,4- oxadiazol-2-yl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.11 (d, J = 7.2Hz, 1H), 7.93 (s, 1H), 7.82 (brs, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.40(t, J = 8.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 5.51-5.26 (m, 1H),4.95-4.81 (m, 2H), 3.88- 3.35 (m, 4H), 2.58 (s, 3H), 2.26-1.90 (m, 2H).Calculated (M + H): 474.14, Found (M + H): 474.1. HPLC purity: 98.07%

Example 265: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of sodium hydride (0.04 g, 1.16 mmol) inN,N-dimethyl formamide was added3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.15 g, 0.35 mmol) at 0° C. and the reaction mixture was stirred atroom temperature for 20 min. Then 3-bromooxetane (0.03 mL, 0.70 mmol)was added and the reaction mixture was heated at 130° C. for 16 h. Thereaction mixture was quenched with ice cold water (10 mL) and extractedwith ethyl acetate (3×25 mL). The combined organic layer wasconcentrated under vacuum to afford crude product, which was purified bysilica gel column chromatography using 4% methanol in dichloromethane toafford title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.027 g, 16% yield) as white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm):8.35-8.33 (m, 1H), 8.24-8.18 (m, 1H), 8.02 (s, 1H), 7.45 (t, J=10 Hz,1H), 7.34 (d, J=7.6 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H), 5.74-5.67 (m, 1H),5.37 (t, J=48.8 Hz, 1H), 5.02-4.94 (m, 4H), 4.87-4.69 (m, 2H), 3.89-3.3(m, 4H), 2.40-1.90 (m, 2H). Calculated (M+H): 482.14, found (M+H):482.1. HPLC purity: 99.41%.

Example 266: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.1 g, 0.23 mmol) in N,N-dimethylformamide (5 mL),3-bromo-1-methyl-1H-1,2,4-triazole (0.06 g, 0.35 mmol), copper(I) iodide(0.045 g, 0.23 mmol) and cesium carbonate (0.23 g, 0.70 mmol) wereadded. The reaction mixture was heated at 100° C. for 6 h undermicrowave conditions. After completion of the reaction, the reactionmixture was quenched with water (20 mL) and extracted with ethyl acetate(3×50 mL). The combined organic layer was washed with brine solution anddried over anhydrous sodium sulfate, filtered and evaporated to affordthe crude product which was purified by silica gel column chromatographyusing 2% methanol in dichloromethane to afford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.011 g, 9.2% yield) as off-white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.63 (s, 1H), 8.28 (d, J=6.4 Hz, 1H), 8.14 (brs, 1H), 7.96 (s,1H), 7.49-7.45 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 5.5-5.25 (m, 1H),4.92-4.75 (m, 2H), 3.95 (s, 3H), 3.88-3.38 (m, 4H), 2.31-2.08 (m, 2H).Calculated (M+H): 507.15, Found (M+H): 507.1, HPLC purity: 98.17%.

TABLE 25 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 267

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1- methyl-1H-1,2,3- triazol-4-yl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.58(s, 1H), 8.19-8.14 (m, 1H), 7.83 (s, 2H), 7.44-7.36 (m, 2H), 6.86 (d, J= 7.6 Hz, 1H), 5.37 (t, J = 50 Hz, 1H), 4.91-4.76 (m, 2H), 4.15 (s, 3H),3.87-3.29 (m, 4H), 2.30-2.09 (m, 2H). Calculated (M + H): 373.12, found(M + H): 373.1, HPLC purity: 99.18% 268

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoro-3-methylazetidin-1-yl)- 2-oxoethyl)-1-(1- methyl-1H-1,2,4-triazol-3-yl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400MHz) δ (ppm): 8.63 (s, 1H), 8.31 (d, J = 6.4 Hz, 1H), 8.13 (brs, 1H),7.97 (s, 1H), 7.49-7.45 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 4.64 (s, 2H),4.39-4.32 (m, 2H), 3.99-3.94 (m, 5H), 1.58 (d, J = 22 Hz, 3H).Calculated (M + H): 507.15, Found (M + H): 507.1, HPLC purity: 94.78%269

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3- methylazetidin-1-yl)2-oxoethyl)-1-(1- methyl-1H-1,2,4- triazol-3-yl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.63(s, 1H), 8.13 (d, J = 6 Hz, 1H), 7,89 (s, 1H), 7.82-7.76 (m, 1H), 7.47(d, J = 7.6 Hz, 1H), 7.37 (t, J = 9.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H),4.64 (s, 2H), 4.41- 4.28 (m, 2H), 4.00-3.94 (m, 5H), 1.58 (d, J = 22 Hz,3H). Calculated (M + H): 507.15, Found (M + H): 507.1, HPLC purity:94.78% 270

3-(3,4- dichlorophenyl)-5-(2- (3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)-1-(1- methyl-1H-1,2,4- triazol-3-yl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.63(s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.82 (dd, J = 2.0 Hz,8.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.3 (d,J = 7.6 Hz, 1H), 4.65 (s, 2H), 4.41-4.29 (m, 2H), 4.0-3.94 (m, 5H) 1.6(d, J = 22 Hz, 3H). Calculated (M + H): 489.1, Found (M + H): 489.1,HPLC purity: 99.78% 271

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3- methylazetidin-1-yl)2-oxoethyl)-1-(1- methyl-1H-1,2,3- triazol-4-yl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.58(s, 1H), 8.15 (d, J = 6 Hz, 1H), 7.84 (s, 2H), 7.45-7.37 (m, 2H), 6.87(d, J = 7.6 Hz, 1H), 4.64 (s, 2H), 4.39-4.32 (m, 2H), 4.15 (s, 3H),4.0-3.95 (m, 2H), 1.6 (d, J = 22 Hz, 3H). Calculated (M + H): 473.12,Found (M + H): 473.1, HPLC purity: 98.92%

Example 272: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

Step 1:

Preparation of2-(3-bromo-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid

To a stirred suspension of ethyl2-(3-bromo-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)acetate(4.0 g, 9.31 mmol) in tetrahydrofuran and water (20 mL, 1:1) at 0° C.,was added lithium hydroxide monohydrate (1.95 g, 46.57 mmol). Thereaction mixture was stirred at room temperature for 1 h. Aftercompletion of the reaction, the reaction mixture was acidified with 1.5N hydrochloric acid (pH 2-3) and extracted with ethyl acetate (2×100mL). The combined organic layer was dried over anhydrous sodium sulfate,filtered and evaporated under vacuum to afford the title compound2-(3-bromo-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5 (4H)-yl)acetic acid (3.2 g,86.0% yield) as a white solid. Calculated (M+H): 401.05, Found (M+H):401.2.

Step 2:

Preparation of 2-(3-bromo-4-oxo-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid

To a stirred suspension of2-(3-bromo-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)aceticacid (2.1 g, 5.23 mmol) in triethylsilane (1.65 mL, 10.47 mmol), wasadded trifluro acetic acid (20.04 mL, 261.84 mmol) at room temperatureand the reaction mixture was stirred at room temperature for 3 h. Aftercompletion of reaction, the reaction mixture was evaporated under vacuumand the residue was diluted with 1 mL of acetonitrile and 16 mL ofammonium hydroxide. The resulting mixture was stirred for 2 h at roomtemperature and acidified with concentrated hydrochloric acid at 0° C.The precipitated product was filtered and dried to afford the titlecompound 2-(3-bromo-4-oxo-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)acetic acid(1.0 g, 70% yield) as a pale brown solid. Calculated (M+H): 270.96,Found (M+H): 271.1.

Step 3:

Preparation of3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of2-(3-bromo-4-oxo-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)acetic acid (2.1 g,5.23 mmol) and 3-fluoropyrrolidine hydrochloride (0.34 g, 2.76 mmol) indichloromethane (10 mL), was added triethylamine (1.28 mL, 9.22 mmol)and the reaction mixture was cooled to 0° C. Then 1-propylphosphonicanhydride (2.19 mL, 3.69 mmol, 50% solution in ethyl acetate) was addedand the reaction mixture was stirred at room temperature for 1.5 h. Thereaction mixture was diluted with dichloromethane (50 mL), washed withwater (20 mL), brine (20 mL), dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford crude product, whichwas purified by silica gel column chromatography using 3% methanol indichloromethane to afford title compound3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.75 g, 62% yield) as brownish solid. Calculated (M+H): 342.02, Found(M+H): 342.0.

Step 4:

Preparation of3-bromo-1-ethyl-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of sodium hydride (0.04 g, 1.16 mmol) inN,N-dimethyl formamide was added3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.2 g, 0.58 mmol) at 0° C. and the reaction mixture was stirred at roomtemperature for 20 min. Then ethyl iodide (0.06 mL, 0.87 mmol) was addedand the reaction mixture was stirred at room temperature for 1.5 h. Thereaction mixture was quenched with ice water (10 mL) and extracted withethyl acetate (3×25 mL). The combined organic layer was concentratedunder vacuum to afford crude product, which was purified by silica gelcolumn chromatography using 3% methanol in dichloromethane to affordtitle compound3-bromo-1-ethyl-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.11 g, 52% yield) as white solid. Calculated (M+H): 370.05, Found(M+H): 370.0.

Step 5:

Preparation of3-(3,4-dichlorophenyl)-1-ethyl-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of3-bromo-1-ethyl-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.11 g, 0.30 mmol) in 1,4-dioxane:water mixture (5 mL, 4:1), was added(3,4-dichlorophenyl)boronic acid (0.08 g, 0.45 mmol) at room temperatureand the resulting mixture was purged with argon for 10 min. To the abovemixture [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (0.01 g, 0.01 mmol) and potassium carbonate(0.126 g, 0.91 mmol) were added and the reaction mixture was stirred at110° C. for 1.5 h. After completion of reaction, the mixture was cooledto room temperature, diluted with water (10 mL) and extracted with ethylacetate (3×25 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated under vacuum to afford crudeproduct, which was purified by silica gel column chromatography using2.5% methanol in dichloromethane to afford the title compound3-(3,4-dichlorophenyl)-1-ethyl-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.03 g, 29%) as a white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.26(d, J=1.2 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.62 (s, 1H), 7.52 (d, J=9.2Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 6.62 (d, J=7.2 Hz, 1H), 5.37 (t, J=49.6Hz, 1H), 4.83-4.71 (m, 2H), 4.15-4.09 (m, 2H), 3.86-3.32 (m, 4H),2.30-1.97 (m, 2H), 1.36 (t, J=6.8 Hz, 3H). Calculated (M+H): 436.09,found (M+H): 436.1, HPLC purity: 96.77%.

TABLE 26 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 273

3-(3,4- dichlorophenyl)- 1-(2-fluoroethyl)- 5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)- 1H-pyrrolo[3,2- c]pyridin-4(5H)- one ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 8.24 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H),7.54 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 6.64 (d, J = 7.6 Hz,1H), 5.37 (t, J = 49.6 Hz, 1H), 4.87-4.67 (m, 4H), 4.44 (d, J = 28 Hz,2H), 3.90-3.37 ((m, 4H), 2.30-1.94 (m, 2H). Calculated (M + H): 454.08,found (M + H): 454.1, HPLC purity: 99.97%

Example 274:3-(3-chloro-4-fluorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

Step-1:

Preparation of3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.2 g, 0.58 mmol) in N,N-dimethylformamide (10 mL), cesium carbonate(0.57 g, 1.75 mmol) and 2,2,2-trifluoroethyl 4-methylbenzenesulfonate(0.22 g, 0.87 mmol) were added and the reaction mixture was heated at90° C. in a orbital shaker for 16 h. The reaction mixture was dilutedwith ice water (10 mL) and extracted with ethyl acetate (3×25 mL). Thecombined organic layer was concentrated under vacuum to afford crudeproduct, which was purified by silica gel column chromatography using2.5% methanol in dichloromethane to afford the title compound3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.08 g, 32% yield) as a white solid. Calculated (M+H): 424.02, Found(M+H): 424.0.

Step-2:

Preparation of3-(3-chloro-4-fluorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.075 g, 0.17 mmol) in 1,4-dioxane:water mixture (5 mL, 4:1) was added(3-chloro-4-fluorophenyl)boronic acid (0.037 g, 0.21 mmol) at roomtemperature and the resulting mixture was purged with argon for 10 min.Then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (0.007 g, 0.008 mmol) and potassium carbonate(0.073 g, 0.53 mmol) were added and the reaction mixture was stirred at100° C. for 1.5 h. After completion of reaction, the mixture was cooledto room temperature, diluted with water (10 mL) and extracted with ethylacetate (3×25 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated under vacuum to afford crudeproduct, which was purified by silica gel column chromatography using 3%methanol in dichloromethane to afford the title compound3-(3-chloro-4-fluorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.016 g, 16% yield) as a white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.08 (dd, J=2.4 Hz, 7.6 Hz, 1H), 7.78-7.70 (m, 1H), 7.51 (s, 1H),7.40-7.33 (m, 2H), 6.74 (d, J=7.6 Hz, 1H), 5.37 (t, J=49.2 Hz, 1H),5.20-5.13 (m, 2H), 4.88-4.72 (m, 2H), 3.90-3.38 (m, 4H), 2.31-1.94 (m,2H). Calculated (M+H): 473.82, found (M+H): 473.82, HPLC purity: 98.74%.

TABLE 27 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 275

3-(3,4-dichlorophenyl)- 5-(2-(3-fluoropyrrolidin- 1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)- 1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.18 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H),7.59- 7.55 (m, 2H), 7.40 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H),5.37 (t, J = 50.0 Hz, 1H), 5.19-5.14 (m, 2H), 4.88-4.72 (m, 2H),3.86-3.40 (m, 4H), 2.30-2.09 (m, 2H). Calculated (M + H): 490.06, found(M + H): 490.0, HPLC purity: 98.24% 276

3-(3,4-dichlorophenyl)- 1-(2,2-difluoroethyl)-5-(2-(3-fluoropyrrolidin-1- yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.21 (d, J = 1.6 Hz, 1H),7.76 (d, J = 8.4 Hz, 1H), 7.57-7.54 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H),6.68 (d, J = 7.2 Hz, 1H), 6.40 (t, J = 54.8 Hz, 1H), 5.37 (t, J = 49.6Hz, 1H), 4.88-4.61 (m, 4H), 3.90- 3.24 (m, 4H), 2.30-1.91 (m, 2H).Calculated (M + H): 472.07, found (M + H): 472.1, HPLC purity: 99.83%

Example 277: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.15 g, 0.35 mmol) in N, N-dimethylformamide (3 mL),2,2,2-trifluoroethyl 4-methylbenzenesulfonate (0.18 g, 0.70 mmol) andcesium carbonate (0.34 g, 1.05 mmol) were added. The reaction mixturewas heated in orbital shaker at 90° C. for 16 h. After completion of thereaction, the reaction mixture was quenched with water (20 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layer waswashed with brine solution (50 mL), dried over anhydrous sodium sulfate,filtered and evaporated to afford the crude product which was purifiedby prep HPLC (column: chemsil C18(250 mm×4.6 mm×5μ), mobile phase (A):0.1% Ammonia in water, mobile phase (B): acetonitrile, flow rate: 1.0mL/min, T/% B: 0/20, 10/80, 25/90, 27/20, 30/20) to afford the titlecompound3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.019 g, 10.6% yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.22 (d, J=6 Hz, 1H), 8.1 (s, 1H), 7.58 (s, 1H), 7.47 (t, J=9.6Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.5-5.25 (m,1H), 5.22-5.15 (m, 2H), 4.88-4.71 (m, 2H), 3.90-3.57 (m, 4H), 2.31-1.96(m, 2H). Calculated (M+H): 508.12, Found (M+H): 508.1, HPLC purity:99.65%.

TABLE 28 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 278

3-(3-chloro-4- fluorophenyl)-1-(2,2- difluoroethyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.10 (d, J = 7.2 Hz, 1H), 7.74 (brs,1H), 7.50 (s, 1H), 7.38-7.33 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H),6.54-6.26 (m, 1H), 5.50-5.25 (m, 1H), 4.87- 4.61 (m, 4H), 3.89-3.30 (m,4H), 2.30-1.90 (m, 2H). Calculated (M + H): 456.10, Found (M + H):456.1. HPLC purity: 99.43% 279

1-(2,2-difluoroethyl)-3- (4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.24 (d, J = 6.8 Hz, 1H), 8.1 (brs,1H), 7.56 (s, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H),6.69 (d, J = 7.2 Hz, 1H), 6.54-6.27 (m, 1H), 5.5-5.25 (m, 1H), 4.88-4.62(m, 4H), 3.90-3.39 (m, 4H), 2.31- 1.93 (m, 2H). Calculated (M + H):490.13, Found (M + H): 490.1, HPLC purity: 98.19% 280

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-1- (2,2,2-trifluoroethyl)- 1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.09 (dd, J = 2.4Hz, 7.2 Hz, 1H), 7.74-7.71 (m, 1H), 7.52 (s, 1H), 7.41-7.34 (m, 2H),6.76 (d, J = 7.6 Hz, 1H), 5.17 (m, 2H), 4.6 (s, 2H), 4.41-4.29 (m, 2H),3.99-3.95 (m, 2H), 1.6 (d, J = 22.4 Hz, 3H). Calculated (M + H): 474.09,Found (M + H): 474.1, HPLC purity: 99.31% 281

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-1-(2- fluoroethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.14 (dd, J = 2.0 Hz, 7.2Hz, 1H), 7.78-7.75 (m, 1H), 7.53 (s, 1H), 7.37-7.31 (m, 2H), 6.65 (d, J= 7.2 Hz, 1H), 4.81- 4.79 (m, 1H), 4.69-4.67 (m, 1H), 4.59 (s, 2H),4.48-4.46 (m, 1H), 4.42-4.29 (m, 3H), 3.99- 3.95 (m, 2H), 1.6 (d, J =22.4 Hz, 3H). Calculated (M + H): 438.11, Found (M + H): 438.1, HPLCpurity: 98.2% 282

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-1- (oxetan-3-yl)-1,5- dihydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.21-8.19 (m, 1H),7.96 (s, 1H), 7.90-7.86 (m, 1H), 7.38-7.32 (m, 2H), 6.64 (d, J = 7.6 Hz,1H), 5.71-5.65 (m, 1H), 5.01-4.91 (m, 4H), 4.59 (s, 2H), 4.39-4.30 (m,2H), 3.98-3.94 (m, 2H), 1.59 (d, J = 22 Hz, 3H). Calculated (M + H):448.12; Found (M + 1): 448.1. HPLC purity 99.64%

Example 283: Preparation of3-(3,4-dichlorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolopyridin-4(5H)-one

Step 1:

Preparation of3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a solution of3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.2 g, 0.58 mmol) in dichloromethane (20 mL), triethylamine (0.25 mL,1.75 mmol) and copper(II)acetate mono hydrate (0.17 g, 0.87 mmol) wereadded and the reaction mixture was purged with air for 1 h. Then1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.18 g, 0.87 mmol) was added and the reaction mixture was heated at 40°C. for 72 h in the presence of air. The reaction mixture was dilutedwith dichloromethane, washed with water, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford the crudeproduct, which was purified by silica gel column chromatography using 5%methanol in dichloromethane to afford the title compound3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.07 g, 31% yield) as off white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.20 (s, 1H), 7.78 (s, 1H), 7.46 (s, 1H), 7.32 (d, J=6.8 Hz, 1H),6.44 (d, J=7.6 Hz, 1H), 5.51-5.26 (m, 1H), 4.82-4.65 (m, 2H), 3.92-3.40(m, 7H), 2.30-1.92 (m, 2H).

Step 2:

Preparation of3-(3,4-dichlorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a stirred suspension of3-bromo-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.07 g, 0.16 mmol) in 1,4-dioxane:water mixture (10 mL, 4:1) was added(3,4-dichlorophenyl)boronic acid (0.050 g, 0.24 mmol) at roomtemperature and the resulting mixture was purged with argon for 10 min.Then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (0.007 g, 0.008 mmol) and potassium carbonate(0.07 g, 0.49 mmol) were added and the reaction mixture was stirred at100° C. for 16 h. After completion of reaction, the mixture was cooledto room temperature, diluted with water (10 mL) and extracted with ethylacetate (3×25 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated under vacuum to afford crudeproduct, which was purified by silica gel column chromatography using 3%methanol in dichloromethane to afford the title compound3-(3,4-dichlorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one(0.022 g, 28% yield) as a off white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.27-8.25 (m, 2H), 7.87-7.84 (m, 2H), 7.73 (s, 1H), 7.56 (d,J=8.4 Hz, 1H), 7.38-7.36 (m, 1H), 6.51 (d, J=7.2 Hz, 1H), 5.5-5.25 (m,1H), 4.91-4.75 (m, 2H), 3.91 (s, 3H), 3.87-3.28 (m, 4H), 2.3-2.6 (m,2H). Calculated (M+H): 488.1, Found (M+H): 488.1, HPLC purity: 98.48%.

TABLE 29 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 284

3-(3,4-dichlorophenyl)-5- (2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)-1-(1-methyl- 1H-pyrazol-4-yl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.26 (d, J = 12.8 Hz, 2H),7.85 (d, J = 9.6 Hz, 2H), 7.74 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.37(d, J = 7.6 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 4.63 (s, 2H), 4.39- 4.31(m, 2H), 3.99-3.91 (m, 5H), 1.6 (d, J = 22 Hz, 3H). Calculated (M + H):488.1, Found (M + H): 488.1, HPLC purity: 97.50% 285

3-(3-chloro-4- fluorophenyl)-1- cyclopropyl-5-(2-(3-fluoro-3-methylazetidin- 1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.16 (d, J = 6.4 Hz, 1H),7.82 (brs, 1H), 7.48 (s, 1H), 7.36-7.3 (m, 2H), 6.65 (d, J = 7.2 Hz,1H), 4.6 (s, 2H), 4.4-4.28 (m, 2H), 3.99-3.95 (m, 2H), 3.47 (brs, 1H),1.6 (d, J = 22 Hz, 3H), 1.04-1.01 (m, 4H). Calculated (M + H): 432.12,Found (M + H): 432.1, HPLC purity: 99.94% 286

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-1-(1- methyl-1H-pyrazol-4-yl)- 1H-pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.24 (s, 1H),8.18 (dd, J = 2.0 Hz, 7.6 Hz, 1H), 7.83-7.82 (m, 2H), 7.67 (s, 1H),7.39-7.35 (m, 2H), 6.52 (d, J = 7.6 Hz, 1H), 4.63 (s, 2H), 4.39-4.31 (m,2H), 4.0-3.91 (m, 5H), 1.6 (d, J = 22.4 Hz, 3H). Calculated (M + H):472.13, Found (M + H): 472.1, HPLC purity: 99.5% 287

1-cyclopropyl-3-(4- fluoro-3- (trifluoromethyl)phenyl)-5-(2-(3-fluoro-3- methylazetidin-1-yl)-2- oxoethyl)-1H-pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.35(d, J = 6.8 Hz, 1H), 8.12 (brs, 1H), 7.53 (s, 1H), 7.42 (t, J = 9.6 Hz,1H), 7.36 (d, J = 7.2 Hz, 1H), 6.67 (d, J = 7.22 Hz, 1H), 4.59 (s, 2H),4.40-4.28 (m, 2H), 3.98 (d, J = 19.6 Hz, 2H), 3.48 (s, 1H), 1.61 (d, J =22 Hz, 3H), 1.04 (d, J = 10.4 Hz, 4H). Calculated (M + H): 466.1; Found(M + H): 466.1. HPLC purity: 99.72% 288

1-cyclopropyl-3-(3,4- dichlorophenyl)-5-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 8.27 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H),7.53 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 6.8 Hz,1H), 4.60 (s, 2H), 4.40-4.30 (m, 2H), 3.99 (d, J = 19.6 Hz, 2H), 3.47(s, 1H), 1.62 (d, J = 22 Hz, 3H), 1.03 (d, J = 9.6 Hz, 4 H). Calculated(M + H): 448.0; Found (M + H): 448.1. HPLC purity: 99.87% 289

1-cyclopropyl-3-(5,6- dichloropyridin-3-yl)-5- (2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-1H- pyrrolo[3,2-c]pyridin- 4(5H)-one¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.84 (s, 1H), 8.77 (s, 1H), 7.74 (s,1H), 7.39 (d, J = 7.2 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H), 4.62 (s, 2H),4.41-4.29 (m, 2H), 3.97 (d, J = 19.2 Hz, 2H), 3.52-3.51 (m, 1H), 1.70(d, J = 22.0 Hz, 3H), 1.15-1.02 (m, 4H). Calculated (M + H): 449.09;Found (M + H): 449.0. HPLC Purity: 98.62% 290

1-cyclopropyl-5-(2-(3- fluoro-3-methylazetidin- 1-yl)-2-oxoethyl)-3-(4-fluoro-3-methylphenyl)- 1H-pyrrolo[3,2- c]pyridin-4(5H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 7.68-7.62 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H),7.28 (s, 1H), 7.027 (t, J = 9.2 Hz, 1H), 6.63 (d, J = 6.8 Hz, 1H), 4.57(s, 2H), 4.39-4.26 (m, 2H), 3.96 (d, J = 19.6 Hz, 2H), 3.46-3.42 (m,1H), 2.22 (s, 3H), 1.59 (d, J = 22.0 Hz, 3H), 1.07-0.97 (m, 4H).Calculated (M + H): 412.18; Found (M + H): 412.2. HPLC Purity: 99.78%291

3-(5-chloro-6- fluoropyridin-3-yl)-1- cyclopropyl-5-(2-(3-fluoro-3-methylazetidin- 1-yl)-2-oxoethyl)-1H- pyrrolo[3,2-c]pyridin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.74 (dd, J = 1.6 Hz, 9.2Hz, 1H), 8.61 (s, 1H), 7.66 (s, 1H), 7.38 (d, J = 6.8 Hz, 1H), 6.69 (d,J = 7.2 Hz, 1H), 4.61 (s, 2H), 4.41- 4.29 (m, 2H), 3.97 (d, J = 19.2 Hz,2H), 3.51-3.48 (m, 1H), 1.60 (d, J = 22.0 Hz, 3 H), 1.09-0.99 (m, 4H).Calculated (M + H): 433.12; Found (M + H): 433.1. HPLC Purity: 99.79%292

3-(4-chloro-3- methylphenyl)-1- cyclopropyl-5-(2-(3-fluoro-3-methylazetidin- 1-yl)-2-oxoethyl)-1,5- dihydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 7.77 (s, 1H), 7.68(d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.33-7.28 (m, 2H), 6.63 (d, J = 7.2Hz, 1H), 4.57 (s, 2H), 4.38-4.26 (m, 2H), 3.98-3.93 (m, 2H), 3.46-3.45(m, 1H), 2.31 (s, 3H), 1.58 (d, J = 22 Hz, 3H), 1.07-1.00 (m, 4H).Calculated (M + H): 428.15; Found (M + 1): 428.0. HPLC purity 99.49% 293

1-cyclopropyl-3-(3,4- dichlorophenyl)-5-(2-(3- fluoro-3-(fluoromethyl)azetidin-1- yl)-2-oxoethyl)-1,5- dihydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.28 (s, 1H), 7.84(d, J = 6.8 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 4.90- 4.72 (m, 2H), 4.62 (s,2H), 4.52-4.37 (m, 2H), 4.13-3.96 (m, 2H), 3.49-3.48 (m, 1H), 1.06-1.01(m, 4H). Calculated (M + H): 466.08; Found (M + 1): 466.1. HPLC purity99.81% 294

1-cyclopropyl-3-(5,6- dichloropyridin-3-yl)-5- (2-(3-ethyl-3-fluorozetidin-1-yl)-2- oxoethyl)-1,5-dihydro- 4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.84 (d, J = 1.6 Hz,1H), 8.77 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H),6.70 (d, J = 7.2 Hz, 1H), 4.63 (s, 2H), 4.41- 4.28 (m, 2H), 4.02-3.88(m, 2H), 3.51-3.49 (m, 1H), 1.92- 1.83 (m, 2H), 1.08-1.02 (m, 4H), 0.90(t, J = 7.6, 3H). Calculated (M + H): 463.1; Found (M + 1): 463.1. HPLCpurity 99.81%

D. Preparation of Quinazolinones Example 295: Preparation of5-(4-chlorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one

Step-1:

Preparation of 5-bromoquinazolin-4(3H)-one

To a solution of 2-amino-6-bromobenzoic acid (0.5 g, 2.3 mmol) inphosphorusoxychloride (10 mL) was added formamide (0.5 mL) and thereaction mixture was heated at 95° C. for 5 h. The reaction mixture wascooled and evaporated to dryness. The residue was taken in ice-water (25mL) and adjusted to pH˜6 using 1N sodium hydroxide solution. Theprecipitated solid was filtered, washed with cold water (25 mL) anddried to obtain the title compound 5-bromoquinazolin-4(3H)-one (0.35 g,crude) as off white solid. Calculated (M+H): 224.96; Found (M+H): 225.2.

Step-2:

Preparation of ethyl 2-(5-bromo-4-oxoquinazolin-3(4H)-yl)acetate

To a stirred solution of 5-bromoquinazolin-4(3H)-one (0.35 g, 1.55 mmol)and ethylbromoacetate (0.34 mL, 3.11 mmol) in acetone was addedpotassium carbonate (0.64 g, 4.66 mmol) and the reaction mixture washeated at 55° C. for 15 h. The reaction mixture was filtered throughcelite and the filtrate was evaporated. The crude product was purifiedby silica gel column chromatography using 40% ethyl acetate in hexane toobtain the title compound ethyl2-(5-bromo-4-oxoquinazolin-3(4H)-yl)acetate (0.4 g, 83% yield) as offwhite solid. Calculated (M+H): 311; Found (M+H): 311.

Step-3:

Preparation of 2-(5-bromo-4-oxoquinazolin-3(4H)-yl)acetic acid

To a stirred solution of ethyl2-(5-bromo-4-oxoquinazolin-3(4H)-yl)acetate (0.4 g, 1.29 mmol) intetrahydrofuran (10 mL) and water (10 mL) mixture, was added lithiumhydroxide monohydrate (0.27 g, 6.43 mmol) at 0° C. and the reactionmixture was stirred at room temperature for 1 h. Then the reactionmixture was evaporated, the residue was diluted with water (20 mL) andacidified with 1.5 N hydrochloric acid solution to pH-2. Theprecipitated solid was filtered, washed with water (50 mL) and dried toobtain the title compound 2-(5-bromo-4-oxoquinazolin-3(4H)-yl)aceticacid (0.28 g, crude) as off white solid. Calculated (M+H): 282.96; Found(M+H): 283.

Step-4:

Preparation of5-bromo-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one

To a stirred solution of 2-(5-bromo-4-oxoquinazolin-3(4H)-yl)acetic acid(0.28 g, 0.989 mmol) in dichloromethane (15 mL) was added triethylamine(0.96 mL, 6.92 mmol) and pyrrolidine (0.16 mL, 1.98 mmol) at roomtemperature. The reaction mixture was cooled to 0° C., 1-propanephosphonic acid cyclic anhydride solution (T₃P) (0.94 mL, 1.48 mmol, 50%solution in ethyl acetate) was added dropwise and the reaction mixturewas stirred at room temperature for 15 h. The reaction mixture wasquenched with water (25 mL) and extracted with dichloromethane (3×25mL). The combined organic extract was washed with brine (25 mL), driedover anhydrous sodium sulfate, filtered and evaporated. The crudeproduct was purified by silica gel column chromatography using 4%methanol in dichloromethane to obtain the title compound5-bromo-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one (0.28 g,85% yield) as off-white solid. Calculated (M+H): 336.03; Found (M+H):336.

Step-5:

Preparation of5-(4-chlorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one

To a stirred suspension of5-bromo-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one (0.1 g,0.29 mmol) and (4-chlorophenyl)boronic acid (0.06 g, 0.38 mmol) in1,4-dioxane (10 mL) and water (3 mL) mixture, was added sodium carbonate(0.095 g, 0.89 mmol) and the resulting mixture was purged with argon for30 minutes. Then bis(triphenylphosphine)palladium(II) dichloride[Pd(PPh₃)₂Cl₂] (0.02 g, 0.02 mmol) was added and the reaction mixturewas heated at 100° C. for 4 h. Then the reaction mixture was cooled toroom temperature, diluted with water (25 mL) and extracted with ethylacetate (3×25 mL). The combined organic extract was washed with brine(25 mL), dried over anhydrous sodium sulfate, filtered and evaporated.The crude product was purified by silica gel column chromatography using4% methanol in dichloromethane to obtain the title compound5-(4-chlorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one(0.105 g, 95% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.24 (s, 1H), 7.84-7.80 (m, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.4Hz, 2H), 7.27-7.24 (m, 3H), 4.68 (s, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.27(t, J=6.8 Hz, 2H), 1.93-1.87 (m, 2H), 1.75-1.72 (m, 2H). Calculated(M+H): 368.1; Found (M+H): 368.1. HPLC Purity: 99.13%.

Example 296: Preparation of5-(4-chlorophenyl)-3-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)quinazolin-4(3H)-one

Step-1:

Preparation of 2-(5-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)aceticacid

To a stirred suspension of ethyl2-(5-bromo-4-oxoquinazolin-3(4H)-yl)acetate (0.1 g, 0.32 mmol) and(4-chlorophenyl)boronic acid (0.065 g, 0.42 mmol) in 1,4-dioxane (6 mL)and water (2 mL) mixture, was added sodium carbonate (0.1 g, 0.96 mmol)and the resulting mixture was purged with argon for 30 minutes. Thenbis(triphenylphosphine)palladium(II) dichloride [Pd(PPh₃)₂Cl₂] (0.022 g,0.03 mmol) was added and the reaction mixture was heated at 100° C. for4 h. Then the reaction mixture was cooled to room temperature andfiltered through celite. The filtrate was diluted with water (25 mL) andextracted with ethyl acetate (3×25 mL) and the organic extract wasdiscarded. The aqueous layer was acidified with 1.5N hydrochloric acidsolution and was extracted with ethyl acetate (3×25 mL). The combinedorganic extract was washed with brine (25 mL), dried over anhydroussodium sulfate, filtered and evaporated to obtain the title compound2-(5-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetic acid (0.1 g,crude) as white solid. Calculated (M+H): 315.05; Found (M+H): 315.1.

Step-2:

Preparation of5-(4-chlorophenyl)-3-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)quinazolin-4(3H)-one

To a stirred solution of2-(5-(4-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetic acid (0.1 g, 0.31mmol) in dichloromethane (10 mL) were added triethylamine (0.265 mL, 1.9mmol) and 3,3-difluoroazetidine hydrochloride (0.062 mL, 0.47 mmol) atroom temperature. The reaction mixture was cooled to 0° C., 1-propanephosphonic acid cyclic anhydride solution (T₃P) (0.3 mL, 0.47 mmol, 50%solution in ethyl acetate) was added dropwise and the reaction mixturewas stirred at room temperature for 15 h. The reaction mixture wasquenched with water (25 mL) and extracted with dichloromethane (3×25mL). The combined organic extract was washed with brine (25 mL), driedover anhydrous sodium sulfate, filtered and evaporated. The crudeproduct was purified by silica gel column chromatography using 4%methanol in dichloromethane to obtain the title compound5-(4-chlorophenyl)-3-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)quinazolin-4(3H)-one(0.075 g, 60%) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.24(s, 1H), 7.85-7.81 (m, 1H), 7.72 (d, J=8 Hz, 1H), 7.39 (d, J=8.4 Hz,2H), 7.29-7.24 (m, 3H), 4.69 (t, J=12 Hz, 2H), 4.64 (s, 2H), 4.32 (t,J=12.4 Hz, 2H). Calculated (M+H): 390.07; Found (M+H): 390.01. HPLCPurity: 98.49%.

TABLE 30 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 297

5-(4-chlorophenyl)-3-(2- oxo-2-(2- (trifluoromethyl) pyrrolidin-1-yl)ethyl)quinazolin- 4(3H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.28-8.25 (m, 1H), 7.85-7.81 (m, 1H), 7.72 (d, J = 8 Hz, 1H), 7.38 (d, J= 8.0 Hz, 2H), 7.29-7.25 (m, 3H), 4.86- 4.77 (m, 2H), 4.71-4.67 (m, 1H),3.63 (bs, 2H), 2.12-1.89 (m, 4H). Calculated (M + H): 436.1; Found (M +H): 436.1, HPLC purity: 98.88% 298

5-(4-chlorophenyl)-3-(2- (2-fluoropyrrolidin-1- yl)-2-oxoethyl)quinazolin- 4(3H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.26(s, 1H), 7.84-7.80 (m, 1H), 7.73-7.71 (m, 1H), 7.38 (d, J = 8.0 Hz, 2H),7.28- 7.24 (m, 3H), 5.37 (t, J = 52.4 Hz, 1H), 4.82-4.64 (m, 2H),3.84-3.28 (m, 4H), 2.24-1.92 (m, 2H). Calculated (M + H): 386.1; Found(M + H): 386.1. HPLC Purity: 98.24%

E. Preparation of Isoquinolinones Example 299: Preparation of8-(4-chloro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)isoquinolin-1(2H)-one

Step-1:

Preparation of 8-bromoisoquinoline 2-oxide

To a solution of 8-bromoisoquinoline (1 g, 4.806 mmol) indichloromethane (30 mL) was added meta-chloroperbenzoic acid (mCPBA)(0.995 g, 5.76 mmol) and the reaction mixture was stirred at roomtemperature for 2 h. After completion of the reaction (monitored byTLC), the reaction mixture was diluted with dichloromethane (30 mL) andwashed with 2M sodium hydroxide solution (2×30 mL). The aqueous layerwas again extracted with dichloromethane (60 mL) and combined organiclayer was dried over anhydrous sodium sulphate, filtered andconcentrated to afford the title compound 8-bromoisoquinoline 2-oxide(1.1 g, crude) as a brownish solid. Calculated (M+H): 223.96; Found(M+H): 223.9.

Step-2:

Preparation of 8-bromoisoquinolin-1(2H)-one

A solution of 8-bromoisoquinoline 2-oxide (0.35 g) and acetic anhydride(5 mL) was refluxed for 3 h. The solution was concentrated, the residuewas dissolved in 2M sodium hydroxide solution (10 mL) and heated at 85°C. for 1 h. The mixture was acidified to pH 6 using 5% aqueous citricacid solution and extracted with dichloromethane (2×30 mL). The combinedorganic layer was dried over anhydrous sodium sulphate, filtered andconcentrated. The obtained residue was triturated with ether to affordthe title compound 8-bromoisoquinolin-1(2H)-one (0.18 g, 51% yield) as abrownish solid. Calculated (M+H): 223.96; Found (M+H): 223.9.

Step-3:

Preparation of ethyl 2-(8-bromo-1-oxoisoquinolin-2(1H)-yl)acetate

A mixture of 8-bromoisoquinolin-1(2H)-one (2.5 g, 11.15 mmol), ethyl2-bromoacetate (2.5 mL, 22.31 mmol) and potassium carbonate (4.62 g,33.47 mmol) in acetone (100 mL) was heated at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Thecrude product was purified by column chromatography using 30% ethylacetate in hexane to afford the title compound ethyl2-(8-bromo-1-oxoisoquinolin-2(1H)-yl)acetate (2.1 g, 61% yield) as abrownish solid. Calculated (M+H): 310.00; Found (M+H): 310.0.

Step-4:

Preparation of2-(8-(4-chloro-3-(trifluoromethyl)phenyl)-1-oxoisoquinolin-2(1H)-yl)aceticacid

A mixture of ethyl 2-(8-bromo-1-oxoisoquinolin-2(1H)-yl)acetate (0.65 g,2.09 mmol), (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (0.705 g,3.14 mmol) and potassium carbonate (0.868 g, 6.28 mmol) in dioxane:watermixture (50 mL, 4:1) was purged with argon for 15 minutes. Thenbis(triphenylphosphine)palladium(II) dichloride (0.171 g, 0.209 mmol)was added and the reaction mixture was heated at 100° C. for 18 h. Thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (30 mL). The aqueous layer was cooled, acidified with 1.5Nhydrochloric acid, extracted with ethyl acetate (100 mL×2) and thecombined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated to afford the title compound2-(8-(4-chloro-3-(trifluoromethyl)phenyl)-1-oxoisoquinolin-2(1H)-yl)aceticacid (0.6 g, 75% yield) as a brownish solid. Calculated (M+H): 382.04;Found (M+H): 382.0.

Step-5:

Preparation of8-(4-chloro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)isoquinolin-1(2H)-one

To a solution of2-(8-(4-chloro-3-(trifluoromethyl)phenyl)-1-oxoisoquinolin-2(1H)-yl)aceticacid (0.06 g, 0.15 mmol), 3-fluoropyrrolidine hydrochloride (0.039 g,0.31 mmol) and triethylamine (0.12 mL, 0.86 mmol) in dichloromethane (10mL) cooled to 0° C., was added 1-propane phosphonic acid cyclicanhydride (T₃P) (0.15 mL, 0.23 mmol, 50% in ethyl acetate) dropwise andthe reaction mixture was stirred at room temperature for 18 h. Thereaction mixture was diluted with dichloromethane (30 mL) and washedwith water (30 mL×2). The organic layer dried over anhydrous sodiumsulphate, filtered and concentrated. The crude was purified by columnchromatography using 2% methanol in dichloromethane to afford the titlecompound8-(4-chloro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)isoquinolin-1(2H)-one(0.03 g, 42% yield) as a off white solid. Calculated (M+H): 453.09;Found (M+H): 453.0. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.72-7.69 (m,2H), 7.62 (t, J=8.4 Hz, 2H), 7.48 (d, J=8 Hz, 1H), 7.38-7.37 (m, 1H),7.25-7.23 (dd, J=2.8 Hz, 5.6 Hz, 1H), 6.66 (d, J=7.2 Hz, 1H), 5.45-5.21(m, 1H), 4.77-4.58 (m, 2H), 3.80-3.20 (m, 4H), 3.21-2.04 (m, 2H). HPLCpurity: 98.72%.

TABLE 31 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 300

8-(4-chloro-3- (trifluoromethyl) phenyl)-2-(2-oxo-2- (pyrrolidin-1-yl)ethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.71-7.68 (m, 2H), 7.64-7.60 (m, 2H), 7.48 (d, J = 8 Hz, 1H), 7.36 (d, J= 7.2 Hz, 1H), 7.24-7.22 (dd, J = 2.4 Hz, 6 Hz, 1H), 6.65 (d, J = 7.2Hz, 1H), 4.61 (s, 2H), 3.41 (t, J = 6.4 Hz, 2H), 3.27-3.22 (m, 2H),1.90-1.83 (m, 2H), 1.76-1.70 (m, 2H). Calculated (M + H): 435.10; Found(M + H): 435.0. HPLC purity: 99.69% 301

8-(4-chloro-3- (trifluoromethyl) phenyl)-2-(2-(3,3- difluoroazetidin-1-yl)-2- oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.73-7.69 (m, 2H), 7.65-7.60 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H),7.37 (d, J = 7.2 Hz, 1H), 7.26-7.24 (m, 1H), 6.68 (d, J = 7.6 Hz, 1H),4.64 (t, J = 11.6 Hz, 2H), 4.56 (s, 2H), 4.27 (t, J = 12 Hz, 2H).Calculated (M + H): 457.07; Found (M + H): 457.0. HPLC purity: 99.25%302

8-(3-chloro-4- fluorophenyl)-2-(2- (3-fluoropyrrolidin- 1-yl)-2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.68-7.65 (m, 2H), 7.36-77.29 (m, 3H), 7.20-7.14 (m, 2H), 6.63 (d, J =7.6 Hz, 1H), 5.46-5.21 (m, 1H), 4.77- 460 (m, 2H), 3.81-3.24 (m, 4H),2.30-1.87 (m, 2H). Calculated (M + H): 403.09; Found (M + H): 403.0.HPLC purity: 98.96% 303

8-(3-chloro-4- fluorophenyl)-2-(2- oxo-2-(pyrrolidin-1-yl)ethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.68-7.65 (m, 2H), 7.36-7.29 (m, 3H), 7.21-7.13 (m, 2H), 6.62 (d, J =6.8 Hz, 1H), 4.61 (s, 2H), 3.42 (t, J = 6.4 Hz, 2H), 3.24 (t, J = 6.4Hz, 2H), 1.91-1.84 (m, 2H), 1.77- 1.70 (m, 2H). Calculated (M + H):385.10; Found M + H: 385.0. HPLC purity: 99.35% 304

8-(3,4- dichlorophenyl)-2- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.70-7.66 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H) 7.41 (d, J = 1.6 Hz, 1H),7.37-7.35 (m, 1H), 7.21-7.18 (m, 1H), 7.16-7.14 (m, 1H), 6.64 (d, J =7.2 Hz, 1H), 5.46-5.21 (m, 1H), 4.77-4.60 (m, 2H), 3.80-3.21 (m, 4H),2.30-1.89 (m, 2H). Calculated (M + H): 419.07; Found (M + H): 419.0.HPLC purity: 99.47% 305

8-(4-chloro-3- fluorophenyl)-2-(2- (3,3- difluoroazetidin-1- yl)-2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.69(d, J = 4.4 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H),7.23- 7.20 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H),4.67-4.62 (m, 2H), 4.57 (s, 2H), 4.32-4.26 (m, 2H). Calculated (M + H):407.07, Found (M + H): 407.0, HPLC purity: 99.23% 306

8-(4-chloro-3- fluorophenyl)-2-(2- (3-fluoropyrrolidin- 1-yl)-2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.69(d, J = 4.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H),7.22- 7.19 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H),5.46-5.22 (m, 1H), 4.77- 4.61 (m, 2H), 3.81-3.21 (m, 4H), 2.22-2.15 (m,1H), 2.12- 1.96 (m, 1H); (Calculated (M + H): 403.09, Found (M + H):403.3, HPLC purity: 99.52% 307

8-(4-chloro-3- fluorophenyl)-2-(2- oxo-2-(pyrrolidin-1-yl)ethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.69(d, J = 4.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H),7.21- 7.19 (m, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 7.2 Hz, 1H),4.61 (s, 2 H), 3.43-3.40 (m, 2H), 3.27-3.23 (m, 2H), 1.91-1.85 (m, 2H),1.77-1.71 (m, 2H); (Calculated (M + H): 385.1, Found (M + H): 385.1,HPLC purity: 99.68% 308

8-(3,4- dichlorophenyl)-2- (2-oxo-2- (pyrrolidin-1-yl)ethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.69-7.66 (m, 2H), 7.53 (d, J = 8 Hz, 1H), 7.40 (d, J = 1.2 Hz, 1H),7.35 (d, J = 7.6 Hz, 1H), 7.21-7.19 (m, 1H), 7.16-7.13 (m, 1H), 6.63 (d,J = 7.2 Hz, 1H), 4.61 (s, 2H), 3.42 (t, J = 6.8 Hz, 2H), 3.24 (t, J =7.2 Hz, 2H), 1.91-1.84 (m, 2H), 1.77-1.70 (m, 2H). Calculated (M + H):401.07; Found (M + H): 401.0. HPLC purity: 99.33% 309

8-(3-chloro-4- fluorophenyl)-2-(2- (3,3- difluoroazetidin-1- yl)-2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.69(d, J = 4 Hz, 2H), 7.36-7.30 (m, 3H), 7.21 (t, J = 4 Hz, 1H), 7.18-7.15(m, 1H), 6.65 (d, J = 7.6 Hz, 1H), 4.64 (t, J = 11.6 Hz, 2H), 4.57 (s,2H), 4.29 (t, J = 12 Hz, 2H). Calculated (M + H): 407.07; Found (M + H):407.0. HPLC purity: 99.28%

Example 310: Preparation of7-(4-chloro-3-(trifluoromethyl)phenyl)-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-one

Step-1:

Preparation of ethyl 2-(7-bromo-1-oxoisoquinolin-2(1H)-yl)acetate

A mixture of 7-bromoisoquinolin-1(2H)-one (1.8 g, 8.03 mmol), ethyl2-bromoacetate (1.8 mL, 16.06 mmol) and potassium carbonate (3.33 g,24.10 mmol) in acetone (50 mL) was heated at 60° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated. Thecrude product was purified by column chromatography using 30% ethylacetate in hexane to afford the title compound ethyl2-(7-bromo-1-oxoisoquinolin-2(1H)-yl)acetate (2.1 g, 84% yield) as offwhite solid. Calculated (M+H): 310.00; Found (M+H): 310.0.

Step-2:

Preparation of2-(7-(4-chloro-3-(trifluoromethyl)phenyl)-1-oxoisoquinolin-2(1H)-yl)aceticacid

A mixture of 2-(7-bromo-1-oxoisoquinolin-2(1H)-yl)acetate (0.2 g, 0.64mmol), (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (0.14 g, 0.64mmol) and potassium carbonate (0.26 g, 1.93 mmol) in dioxane:watermixture (10 mL, 4:1) was purged with argon for 15 minutes. Then[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (Pd(dppf)Cl₂.DCM)(0.026 g, 0.03 mmol) was addedand the reaction mixture was heated at 100° C. for 18 h. The reactionmixture was diluted with water (25 mL) and extracted with ethyl acetate(30 mL). The aqueous layer was cooled, acidified with 1.5N hydrochloricacid, extracted with ethyl acetate (100 mL×2) and the combined organiclayer was dried over anhydrous sodium sulphate, filtered andconcentrated to afford the title compound2-(7-(4-chloro-3-(trifluoromethyl)phenyl)-1-oxoisoquinolin-2(1H)-yl)aceticacid (0.21 g, crude) as a brownish solid. Calculated (M+H): 382.04;Found (M+H): 382.0.

Step-3:

Preparation of7-(4-chloro-3-(trifluoromethyl)phenyl)-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-one

To a solution of2-(7-(4-chloro-3-(trifluoromethyl)phenyl)-1-oxoisoquinolin-2(1H)-yl)aceticacid (0.07 g, 0.16 mmol), pyrrolidine (0.011 g, 0.16 mmol) andtriethylamine (0.18 mL, 1.33 mmol) in dichloromethane (10 mL) cooled to0° C., was added 1-propane phosphonic acid cyclic anhydride (T₃P) (0.21mL, 0.33 mmol, 50% in ethyl acetate) dropwise and the reaction mixturewas stirred at room temperature for 18 h. The reaction mixture wasdiluted with dichloromethane (30 mL) and washed with water (30 mL×2).The organic layer dried over anhydrous sodium sulphate, filtered andconcentrated. The crude was purified by column chromatography using 2%methanol in dichloromethane to afford the title compound7-(4-chloro-3-(trifluoromethyl)phenyl)-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-one(0.03 g, 42% yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.44 (s, 1H), 8.10 (s, 2H), 8.06 (d, J=8.4 Hz, 1H), 7.82 (d,J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 6.65 (d,J=7.2 Hz, 1H), 4.78 (s, 2H), 3.54 (d, J=6.4 Hz, 2H), 3.32-3.26 (m, 2H),1.95-1.90 (m, 2H), 1.82-1.77 (m, 2H); Calculated (M+H): 435.1, Found(M+H): 435.1; HPLC purity: 99.59%.

TABLE 32 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical data 311

7-(4-chloro-3- (trifluoromethyl)phenyl)- 2-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.44 (s, 1H), 8.10 (s, 2H), 8.06 (d, J = 8.4 Hz,1H), 7.82 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.40 (d, J =6.8 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 5.39 (t, J = 50.4 Hz, 1H),4.91-4.73 (m, 2 H), 3.94-3.31 (m, 4H), 2.30-1.96 (m, 2H). Calculated(M + H): 453.09, Found (M + H): 453.1, HPLC purity: 96.54% 312

7-(4-chloro-3- (trifluoromethyl)phenyl)- 2-(2-(3,3-difluoroazetidin-1-yl)- 2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.45 (s, 1H), 8.13-8.07 (m, 3H), 7.83-7.78 (m,2H), 7.42 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 4.78 (t, J = 12Hz, 2H), 4.70 (s, 2H), 4.35 (t, J = 12 Hz, 2H). Calculated (M + H):457.07, Found (M + H): 457.0. HPLC purity: 99.57% 313

7-(4-fluoro-3- (trifluoromethyl) phenyl)-2-(2-oxo-2- (pyrrolidin-1-yl)ethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.41(d, J = 1.6 Hz, 1H), 8.12- 8.03 (m, 3H), 7.77 (d, J = 8.4 Hz, 1H), 7.62(t, J = 10 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 6.65 (d, J = 4.4 Hz, 1H),4.78 (s, 2H), 3.54 (t, J = 6.8 Hz, 2H), 3.32- 3.28 (m, 2H), 1.97-1.90(m, 2H), 1.82-1.75 (m, 2H). Calculated (M + H): 419.13, Found (M + H):419.1. HPLC purity: 98.83% 314

7-(4-fluoro-3- (trifluoromethyl) phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.41 (s, 1H), 8.09-8.03 (m, 3H), 7.77 (d, J = 8Hz, 1H), 7.62 (t, J = 9.6 Hz, 1H), 7.40 (d, J = 6.8 Hz, 1H), 6.66 (d, J= 7.2 Hz, 1H), 5.39 (t, J = 50 Hz, 1H), 4.90-4.73 (m, 2H), 3.94-3.34 (m,4H), 2.30-1.96 (m, 2H). Calculated (M + H): 437.12, Found (M + H):437.1. HPLC purity: 96.69% 315

7-(3,4-dichlorophenyl)- 2-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)isoquinolin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.40 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 8.00 (s, 1H), 7.68- 7.73 (m,3H), 7.38 (d, J = 6.0 Hz, 1H), 6.64 (d, J = 7.2 Hz, 1 H), 5.38 (t, J =49.2 Hz, 1H), 4.90-4.73 (m, 2 H), 3.93-3.42 (m, 4H), 2.29-1.97 (m, 2H).Calculated (M + H): 419.07, Found (M + H): 419.0. HPLC purity: 97.89%316

7-(3,4-dichlorophenyl)- 2-(2-oxo-2-(pyrrolidin- 1-yl)ethyl)isoquinolin-1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.41 (s, 1H), 8.06 (d, J =8.4 Hz, 1H), 8.00 (s, 1H), 7.76- 7.71 (m, 3H), 7.37 (d, J = 7.2 Hz, 1H),6.64 (d, J = 7.2 Hz, 1H), 4.77 (s, 2H), 3.54 (t, J = 6.4 Hz, 2H),3.32-3.26 (m, 2H), 1.95- 1.90 (m, 2H), 1.82-1.75 (m, 2H). Calculated(M + H): 401.07, Found (M + H): 401.1. HPLC purity: 98.38%

F. Preparation of Pyrazolopyrimidinones Example 317: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

Step-1:

Preparation of tert-butyl3-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate

To a stirred solution of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(0.1 g, 0.465 mmol) and N,N-dimethylpyridin-4-amine (0.005 g, 0.0465mmol) in N,N-dimethyl formamide (6 mL) cooled to 0° C. was addeddi-tert-butyl dicarbonate (0.1 mL, 0.465 mmol) and then the reactionmixture was stirred at room temperature for 3 h. The reaction mixturewas diluted with ice cold water (30 mL) with 1-2 mL of diethyl ether andstirred for 1 h at 0° C. The solid formed was filtered, washed withether (2×5 mL) and dried under vacuum to get the title compoundtert-butyl3-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(0.13 g, crude) as white solid, which was used for next step withoutfurther purification. Calculated (M+H): 315; Found (M+H): 315.

Step-2:

Preparation of tert-butyl3-bromo-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate

To a stirred solution of tert-butyl3-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(0.13 g, 0.412 mmol) in dry acetone (4 mL) was added potassium carbonate(1.7 g, 1.23 mmol) followed by 2-chloro-1-(pyrrolidin-1-yl)ethanone(0.09 g, 0.619 mmol) at room temperature and the reaction mixture washeated at reflux for 3 h. The reaction mixture was concentrated, dilutedwith water and extracted with ethyl acetate (3×10 mL). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to get crude compound which was washed with pentane (2×20mL) to get the title compound tert-butyl3-bromo-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(0.085 g, 48.6% yield) as off white solid. Calculated (M+H): 426.07;Found (M+H): 326 (de-Boc mass observed).

Step-3:

Preparation of tert-butyl3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate

To a stirred solution of tert-butyl3-bromo-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(0.085 g, 0.199 mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronicacid in dioxane: water mixture (5 mL, 4:1) was added sodium carbonate(0.064 g, 0.597 mmol) and the reaction mixture was purged with argon for15 minutes. Then Bis(triphenylphosphine)palladium(II) dichloride (0.014g, 0.019 mmol) was added and the reaction mixture heated at 100° C. for2 h. The reaction mixture was cooled to room temperature, diluted withwater and extracted with ethyl acetate (4×25 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto get crude compound which was purified by silica gel columnchromatography using 4% methanol in dichloromethane to get the titlecompound tert-butyl3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(0.01 g, 11.90% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 14.2 (s, 1H), 9.90 (s, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.25 (s, 1H),7.80 (d, J=8.8 Hz, 1H), 4.84 (s, 2H), 3.55-3.52 (m, 2H), 3.32-3.22 (m,2H), 2.04-1.91 (m, 2H), 1.82-1.76 (m, 2H). Calculated (M+H): 426.09;Found (M+H): 426. HPLC purity: 99.83%.

Example 318: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

Step-1:

Preparation of tert-butyl3-bromo-5-(2-ethoxy-2-oxoethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate

To a stirred solution of tert-butyl3-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(1.1 g, 3.49 mmol) in dry acetone (15 ml) at room temperature was addedpotassium carbonate (1.44 g, 10.47 mmol) followed byethyl-2-bromoacetate (0.58 mL, 5.23 mmol) and the reaction mixture washeated at reflux for 3 h. The reaction mixture concentrated, dilutedwith water and extracted with ethyl acetate (4×50 mL). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to get the crude compound which was purified by silica gelcolumn chromatography using 100% dichloromethane to get the titlecompound tert-butyl3-bromo-5-(2-ethoxy-2-oxoethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(0.67 g, 47.85% yield) as yellow solid. Calculated (M+H): 401.04; Found(M+H): 301.2 (de-Boc mass observed).

Step-2:

Preparation of2-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)aceticacid

To a stirred solution of tert-butyl3-bromo-5-(2-ethoxy-2-oxoethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(0.67 g, 1.67 mmol) and (4-chloro-3-(trifluoromethyl) phenyl)boronicacid (0.449 g, 2.00 mmol) in dioxane:water mixture (10 mL, 4:1) wasadded potassium carbonate (0.69 g, 5.01 mmol) and the reaction mixturewas purged with argon for 15 minutes. Then[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane complex (pd(dppf)Cl₂.CH₂Cl₂) (0.068 g, 0.083 mmol) wasadded and the reaction mixture was heated at 110° C. for 16 h. Thereaction mixture was concentrated, the residue was diluted with water(30 mL) and extracted with ethyl acetate (30 mL). The aqueous layer wasacidified to pH˜2 with 1.5N hydrochloric acid solution under cooling toget precipitation. The precipitate was filtered, washed with pentane(2×10 mL), diethyl ether (2×10 mL) and dried under vacuum to get thetitle compound2-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)aceticacid (0.32 g, 47.8% yield) as brown solid. Calculated (M+H): 373.02;Found (M+H): 373.

Step-3:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-((3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

To a stirred solution of2-(3-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)aceticacid (0.12 g, 0.322 mmol) in dichloromethane (10 mL) was addedtriethylamine (0.08 mL, 0.644 mmol) at room temperature and stirred for10 minutes. Then 3-fluoropyrrolidine hydrochloride salt (0.048 g, 0.388mmol) was added. Then the reaction mixture was cooled to 0° C.,1-Propanephosphonic anhydride solution (T₃P) (0.3 mL, 0.483 mmol, 50% inethyl acetate) was added and stirred at room temperature for 16 h. Thesolution was diluted with water and extracted with dichloromethane (4×50mL). The combined organic layer was dried over anhydrous sodium sulfate,filtered and concentrated to get crude compound which was purified bysilica gel column chromatography using 3% methanol in dichloromethane toafford the title compound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(0.015 g, 10.4% yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm) 14.20 (s, 1H), 8.99 (s, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.28 (s, 1H),7.80 (d, J=8.4 Hz, 1H), 5.52-5.26 (m, 1H), 4.98-4.80 (m, 2H), 3.90-3.27(m, 4H), 2.23-2.11 (m, 2H). Calculated (M+H): 444.08; Found (M+H): 444.HPLC purity: 99.36%.

Ex. No. Structure Name Analytical data 319

3-(4-chloro-3- fluorophenyl)-5-(2- oxo-2-(pyrrolidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4(5H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm):14.12 (s, 1H), 8.49 (d, 11.2 Hz, 1H), 8.26 (s, 1H), 8.21 (d, 8.4 Hz,1H), 7.65 (t, 7.6 Hz, 1H), 4.82 (s, 2H), 3.53 (t, 6.8 Hz, 2H), 3.30 (t,6.4 Hz, 2H), 1.96-1.92 (m, 2H), 1.81-1.70 (m, 2H); Calculated (M − H):374.09, Found (M − H): 374.0. HPLC purity: 99.31% 320

3-(4-Chloro-3- trifluoromethyl- phenyl)-5-[2-(3,3-difluoro-azetidin-1-yl)- 2-oxo-ethyl]-1,5- dihydro-pyrazolo[3,4-d]pyrimidin-4-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 14.22 (s, 1H), 9.00(s, 1H), 8.58 (d, J = 8 Hz, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H),4.78 (s, 4H), 4.36 (m, 2H). Calculated (M + H): 448.05; Found (M + H):448.0. HPLC purity: 97.49%

G. Preparation of Pyrazolopyrazinones Example 321: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl) pyrazolo [1,5-a]pyrazin-4(5H)-one

Step 1:

Preparation of 4-bromo-1H-pyrazole-3-carboxylic acid

To a stirred solution of 1H-pyrazole-3-carboxylic acid (2.0 g, 17.85mmol) in acetic acid (50 mL), bromine (1.2 mL, 23.21 mmol) was added at0° C. and the reaction mixture was stirred at room temperature for 16 h.The reaction mixture was diluted with water (150 mL) and extracted withethyl acetate (3×100 mL). The combined organic layer was washed withbrine solution, dried over anhydrous sodium sulfate, filtered andconcentrated to afford the title compound4-bromo-1H-pyrazole-3-carboxylic acid (3.4 g, crude) as off-white solid.Calculated (M+H): 190.94; Found (M+H): 191.0.

Step 2:

Preparation of 4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-3-carboxamide

To a stirred solution of 4-bromo-1H-pyrazole-3-carboxylic acid (3.4 g,17.8 mmol) in dichloromethane (100 mL) were added triethylamine (12.42mL, 89.00 mmol) and 2,2-dimethoxyethanamine (2.9 mL, 26.70 mmol) at roomtemperature. The reaction mixture was cooled to 0° C. and1-propanephosphonic anhydride solution (T₃P) (15.89 mL, 26.70 mmol, 50%in ethyl acetate) was added and the reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (200mL) and extract with dichloromethane (3×100 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto afford the title compound4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-3-carboxamide (3.6 g, crude)as a white solid. Calculated (M−H): 276.01; Found (M−H): 276.0.

Step 3:

Preparation of 3-bromo-7-hydroxy-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one

To a stirred solution of4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-3-carboxamide (3.6 g, 12.94mmol) in 1,4-dioxane (100 mL), concentrated hydrochloric acid was addedslowly and solution was stirred at room temperature for 1 h. Thereaction mixture was quenched with ice water (200 mL), extracted withethyl acetate (3×100 mL) and the combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to afford the titlecompound 3-bromo-7-hydroxy-6,7-dihydropyrazolo [1,5-a] pyrazin-4(5H)-one(3.0 g, crude) as a white solid. Calculated (M+H): 231.96; Found (M+H):232.0.

Step 4:

Preparation of 3-bromopyrazolo [1,5-a] pyrazin-4(5H)-one

To a stirred solution of3-bromo-7-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (3.0 g,12.94 mmol) in 1,4-dioxane (60 mL), concentrated hydrochloric acid wasadded slowly and the reaction mixture was heated at 100° C. for 16 h.After completion of the reaction (monitored by TLC), the reactionmixture was diluted with ice water (200 mL) and extracted with ethylacetate (3×100 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated to afford the crude compoundwhich was triturated with ether:n-pentane mixture to afford the titlecompound 3-bromopyrazolo [1,5-a] pyrazin-4(5H)-one as a off-white solid(0.7 g, crude). Calculated (M+H): 213.96; Found (M+H): 214.0.

Step 5:

Preparation of ethyl 2-(3-bromo-4-oxopyrazolo [1,5-a] pyrazin-5(4H)-yl)acetate

To a solution of 3-bromopyrazolo [1,5-a] pyrazin-4(5H)-one (0.5 g, 2.33mmol) in acetone (20 mL) was added potassium carbonate (0.97 g, 7.00mmol) followed by ethylbromoacetate (0.51 mL, 4.67 mmol). The reactionmixture was heated at 55° C. for 16 h. After completion of the reaction(monitored by TLC), the reaction mixture was filtered and the filtratewas concentrated under vacuum. The crude product was purified by silicagel column chromatography using 2% methanol in dichloromethane to affordthe title compound ethyl2-(3-bromo-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)acetate (0.7 g, 100%yield) as a off-white solid. Calculated (M+H): 299.99; Found (M+H):300.0.

Step 6:

Preparation of 2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)acetic acid

To a solution of 2-(3-bromo-4-oxopyrazolo [1,5-a] pyrazin-5(4H)-yl)acetate (0.5 g, 1.66 mmol) in 1,4-dioxane:water mixture (4:1, 30 mL),potassium carbonate (0.69 g, 4.99 mmol) and(4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (0.52 g, 2.49 mmol)were added and the reaction mixture was purged with argon for 10 min.Then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (Pd(dppf)Cl₂.DCM) (0.14 g, 0.166 mmol) wasadded and the reaction mixture was heated at 100° C. for 16 h. Thereaction mixture was diluted with water (50 mL) and it was washed withethyl acetate (2×30 mL). The aqueous layer pH was adjusted to acidic byusing 1.5N hydrochloric acid solution and extracted with ethyl acetate(2×100 mL). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated. The crude was purified by silicagel column chromatography using 5% methanol in dichloromethane to afford2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)aceticacid (0.48 g, 81.35% yield) as a off-white solid. Calculated (M+H):356.06; Found (M+H): 356.0.

Step 7:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)aceticacid (0.12 g, 0.33 mmol) in dichloromethane (10 mL) was addedtriethylamine (0.23 ml, 1.69 mmol) at room temperature followed by3-fluoropyrrolidine hydrochloride (0.063 g, 0.50 mmol). The reactionmixture was cooled to 0° C., 1-propanephosphonic anhydride solution(T₃P) (0.4 ml, 0.676 mmol, 50% in ethyl acetate) was added and stirredat room temperature for 16 h. The reaction mixture was diluted withwater (50 mL) and extracted with dichloromethane (2×50 mL). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude product was purified by silica gel columnchromatography using 3% methanol in dichloromethane to afford3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrazolo[1,5-a]pyrazin-4(5H)-one(0.065 g, 45% yield) as a off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.33 (s, 1H), 8.30 (d, J=5.6 Hz, 1H), 8.12-8.15 (m, 1H), 7.808(d, J=6 Hz, 1H), 7.53 (t, J=9.2 Hz, 1H), 7.09-7.11 (m, 1H), 5.38 (m,1H), 4.69-4.88 (m, 2H), 3.31-3.88 (m, 4H), 1.99-2.30 (m, 2H). CalculatedM+H: 427.11 Found M+H: 427.1. HPLC purity: 99.7%.

TABLE 33 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 322

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-(3-fluoroazetidin-1-yl)-2- oxoethyl)pyrazolo[1,5- a]pyrazin-4(5H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.33 (s, 1H), 8.30-8.29 (m, 1H),8.15-8.122 (m, 1H), 7.813 (d, J = 5.6 Hz, 1H), 7.53 (t, J = 10.4 Hz,1H), 7.09 (d, J = 5.6 Hz, 1H), 5.525- 5.35 (m, 1H), 4.61 (s, 2H),4.57-3.89 (m, 4H). Calculated M + H: 413.1; Found M + H: 413.1; HPLCpurity: 99.58% 323

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 5-(2-oxo-2- (pyrrolidin-1-yl)ethyl)pyrazolo[1,5- a]pyrazin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.29 (s, 1H), 8.31-8.29 (m, 1H), 8.152-8.125 (m, 1H), 7.79 (d, J= 5.2 Hz, 1H), 7.53 (t, J = 9.6 Hz, 1H), 7.09 (d, J = 6.0 Hz, 1H), 4.72(s, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.29 (t, J = 6.8 Hz, 2H), 1.88-1.95(m, 2H), 1.74-1.807 (m, 2H) Calculated (M + H): 409.12; Found (M + H):409.1; HPLC purity: 99.88% 324

5-(2-(3,3- difluoroazetidin-1-yl)- 2-oxoethyl)-3-(4- fluoro-3-(trifluoromethyl)phenyl) pyrazolo[1,5- a]pyrazin-4(5H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.34 (s, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.14-8.12(m, 1H), 7.82 (d, J = 6 Hz, 1H), 7.53 (t, J = 10.0 Hz, 1H), 7.09 (d, J =5.6 Hz, 1H), 4.74 (t, J = 11.6 Hz, 2H), 4.68 (s, 2H), 4.34 (t, J = 12Hz, 2H). Calculated (M + H): 431.09; Found (M + H): 431.1; HPLC purity:99.78% 325

3-(3,4-dichlorophenyl)- 5-(2-(3,3- difluoroazetidin-1-yl)- 2-oxoethyl)pyrazolo[1,5- a]pyrazin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.33 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.84-7.81 (m, 2H), 7.63(d, J = 8.4 Hz, 1H), 7.09 (d, J = 6.4 Hz, 1H), 4.74 (t, J = 12.4 Hz,2H), 4.68 (s, 2H), 4.35 (t, J = 12.4 Hz, 2H). Calculated (M + H):413.03; Found (M + H): 413.0; HPLC purity: 97.39% 326

3-(3,4-dichlorophenyl)- 5-(2-oxo-2-(pyrrolidin- 1-yl)ethyl)pyrazolo[1,5- a]pyrazin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.32 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 2.4 Hz, 8.0Hz, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.09 (d, J= 6.0 Hz, 1H), 4.72 (s, 2H), 3.49 (t, J = 6.8 Hz, 2H), 3.29 (t, J = 10Hz, 2H), 1.95-1.89 (m, 2H), 1.74-1.81 (m, 2H) Calculated (M + H):391.07; Found (M + H): 391.0; HPLC purity: 98.52% 327

3-(3,4-dichlorophenyl)- 5-(2-(3- fluoropyrrolidin-1-yl)- 2-oxoethyl)pyrazolo[1,5- a]pyrazin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.33 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.84-7.79 (m, 2H), 7.63(d, J = 8.4 Hz, 1H), 7.12-7.09 (m, 1H), 5.37 (m, 1H), 4.87-4.69 (m, 2H), 3.88-3.39 (m, 4H), 1.89-1.69 (m, 2H). Calculated (M + H): 409.06;Found (M + H): 409.0; HPLC purity: 97.40% 328

3-(3-chloro-4- fluorophenyl)-5-(2- (3,3-difluoroazetidin-1- yl)-2-oxoethyl)pyrazolo[1,5- a]pyrazin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm); 8.29 (s, 1H), 8.14-8.12 (m, 1H), 7.83-7.80 (m, 2H), 7.46- 7.41(m, 1H), 7.08 (d, J = 6.4 Hz, 1H), 4.74 (t, J = 12.4 Hz, 2H), 4.68 (s,2H), 4.35 (t, J = 12.0 Hz, 2H). Calculated (M + H): 397.06; Found (M +1): 397.0. HPLC purity 99.88% 329

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoro-3- methylazetidin-1-yl)-2-oxoethyl)pyrazolo[1,5- a]pyrazin-4(5H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm); 8.28 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.80-7.79 (m, 2H),7.45-7.41 (m, 1H), 7.08 (d, J = 6.0 Hz, 1H), 4.61 (s, 2H), 4.41-4.28 (m,2H), 3.99 (d, J = 20.0 Hz, 2H), 1.59 (d, J = 21.6 Hz, 3H). Calculated(M + H): 393.09; Found (M + 1): 393.1. HPLC purity 99.21%

H. Preparation of Thioenotriazinones Example 330: Preparation of5-(3-chloro-4-fluorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one

Step-1:

Preparation of 2-amino-4-(3-chloro-4-fluorophenyl)thiophene-3-carboxylicacid

To a solution of ethyl2-amino-4-(3-chloro-4-fluorophenyl)thiophene-3-carboxylate (0.6 g, 4.81mmol) in ethanol (5 mL) was added 3N sodium hydroxide solution (0.5 mL)and the reaction mixture was stirred at 80° C. for 2 h. After completionof the reaction (monitored by TLC), the reaction mixture was evaporated,diluted with water (30 ml) and acidified with 1.5M hydrochloric acid topH 2-4. The precipitated solid was filtered, washed with water, anddried to afford the title compound2-amino-4-(3-chloro-4-fluorophenyl)thiophene-3-carboxylic acid (0.45 g,82% yield) as a brownish solid. Calculated M+H: 271.99; Found M+H:272.0.

Step-2:

Preparation of2-amino-4-(3-chloro-4-fluorophenyl)thiophene-3-carboxamide

To a solution of2-amino-4-(3-chloro-4-fluorophenyl)thiophene-3-carboxylic acid (0.45 g,1.66 mmol) in dimethylformamide (DMF) was added1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI.HCl) (0.47 g, 2.49mmol), 1-hydroxybenzotriazole (HOBt) (0.38 g, 2.49 mmol), triethylamine(0.69 mL, 4.98 mmol) and ammonium chloride (0.18 g, 3.32 mmol) andstirred at room temperature for 12 h. After completion of the reaction(monitored by TLC), the reaction mixture was diluted with water andextracted with ethyl acetate (2×30 mL). The combined organic layers weredried over anhydrous sodium sulphate, filtered and concentrated toafford the crude product, which was purified by silica gel (60-120)column chromatography using 40% ethyl acetate in hexane to afford thetitle compound2-amino-4-(3-chloro-4-fluorophenyl)thiophene-3-carboxamide (0.3 g, 65%yield) as a brownish solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.00 (s,2H), 7.46 (d, J=7.2 Hz, 1H), 7.28 (s, 1H), 7.17 (t, J=8.4 Hz, 1H), 6.36(s, 2H).

Step-3:

Preparation of5-(3-chloro-4-fluorophenyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one

To a solution of2-amino-4-(3-chloro-4-fluorophenyl)thiophene-3-carboxamide (0.3 g, 1.11mmol), in concentrated sulfuric acid (3 mL) was added a solution ofsodium nitrite (0.15 g, 2.22 mmol) in concentrated sulfuric acid (2 mL)slowly at 0° C. and stirred at 0° C. for 2 h. The reaction mixture wasdiluted with water, the precipitated solid was filtered, washed withwater and dried under vacuum to afford the title compound5-(3-chloro-4-fluorophenyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one (0.15g, 48% yield) as a brownish solid. Calculated M−H: 279.98; Found M−H:280.0.

Step-4:

Preparation of5-(3-chloro-4-fluorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one

To a solution of5-(3-chloro-4-fluorophenyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one (0.1 g,0.36 mmol) in acetone (4 mL) was added2-chloro-1-(pyrrolidin-1-yl)ethanone (0.1 g, 0.71 mmol) and potassiumcarbonate (0.14 g, 1.07 mmol) at room temperature and heated to refluxfor 2 h. After completion of the reaction (monitored by TLC), thereaction mixture was evaporated, diluted with water (30 mL), extractedwith ethyl acetate (2×30 mL). The combined organic layers were washedwith water, dried over anhydrous sodium sulfate, filtered andconcentrated. The crude was purified by silica gel (60-120) columnchromatography using 40% ethyl acetate in hexane to afford the titlecompound5-(3-chloro-4-fluorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one(0.02 g, 14% yield) as a brownish solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.27 (s, 1H), 7.82 (d, J=5.2 Hz, 1H), 7.58 (s, 1H), 7.47 (t,J=9.2 Hz, 1H), 5.24 (s, 2H), 3.56 (t, J=6.8 Hz, 2H), 1.91 (t, J=6.8 Hz,2H), 1.77 (t, =6.8 Hz, 2H) (Two protons are merged with solvent peak).Calculated (M+H): 393.05, Found (M+H): 393.0, HPLC purity: 99.35%.

TABLE 34 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 331

5-(4-chloro-3- (trifluoromethyl) phenyl)-3-(2-oxo-2- (pyrrolidin-1-yl)ethyl)thieno[2,3- d][1,2,3]triazin- 4(3H)-one ¹H-NMR (DMSO-d₆, 400MHz) δ (ppm): 8.38 (s, 1H), 8.07 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.79(d, J = 8.0 Hz, 1H), 5.24 (s, 2H), 3.56 (m, 2H), 1.91 (m, 2H), 1.77 (m,2H) (Two protons are merged with solvent peak). Calculated (M + H):443.05, Found (M + H): 443.3, HPLC purity: 99.35%.

Example 332: Preparation of5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one

Step 1:

Preparation of ethyl2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d][1,2,3]triazin-3(4H)-yl)acetate

To a solution of5-(4-chloro-3-(trifluoromethyl)phenyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one(0.35 g, 1.06 mmol) in acetone (10 mL) was added ethyl 2-bromoacetate(0.35 g, 2.12 mmol) and potassium carbonate (0.43 g, 3.18 mmol) at roomtemperature and the reaction mixture was heated to 55° C. for 30 min.The reaction mixture was cooled to room temperature, filtered throughcelite bed, washed with acetone. The filtrate was concentrated undervacuum and crude was purified by silica gel (60-120) columnchromatography using 30% ethyl acetate in hexane to afford title productethyl2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d][1,2,3]triazin-3(4H)-yl)acetate(0.35 g, 79% yield) as off-white solid. Calculated (M+H): 418.02; Found(M+H): 418.0.

Step 2:

Preparation of2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d][1,2,3]triazin-3(4H)-yl)aceticacid

To a mixture of 5 ethyl2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d][1,2,3]triazin-3(4H)-yl)acetate(0.35 g, 0.84 mmol) in tetrahydrofuran (4 mL) and water (2 mL) was addedlithium hydroxide monohydrate (0.1 g, 2.58 mmol) at 0° C. and thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with water, acidified with 1.5M hydrochloric acid topH 2 to 3, the precipitated solid was filtered, washed with water anddried under vacuum to afford the title compound2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d][1,2,3]triazin-3(4H)-yl)aceticacid (0.3 g, 92% yield) as off-white solid. Calculated M+H: 389.98,Found M+H: 389.9.

Step 3:

Preparation of5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one

To a stirred solution of2-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d][1,2,3]triazin-3(4H)-yl)aceticacid (0.07 g, 0.18 mmol) in dichloromethane (3 mL) was addedtriethylamine (0.07 mL, 0.54 mmol), 3-fluoropyrrolidine hydrochloride(0.05 g, 0.36 mmol) at room temperature. The reaction mixture wasallowed to cool to 0° C., was added 1-propanephosphonic anhydride (50%solution in ethyl acetate) (0.22 mL, 0.36 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was diluted withdichloromethane, washed with water (2×25 mL), dried over anhydroussodium sulfate, filtered, concentrated under vacuum to afford the crudecompound, which was purified by silica gel (60-120) columnchromatography using 50% ethyl acetate in hexane to afford the titlecompound5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[2,3-d][1,2,3]triazin-4(3H)-one(0.03 g, 36% yield) as off white solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 8.39 (s, 1H), 8.07 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.79 (d,J=8.4 Hz, 1H), 5.49-5.18 (m, 3H), 4.0-3.59 (m, 4H), 2.30-1.96 (m, 2H).Calculated (M+H): 461.04, Found (M+H): 461.0, HPLC purity 99.82%.

TABLE 35 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data 333

5-(4-chloro-3- (trifluoromethyl)phenyl)- 3-(2-(3,3-difluoroazetidin-1-yl)- 2-oxoethyl)thieno[2,3- d][1,2,3]triazin-4(3H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.40 (s, 1H), 8.07 (s, 1H), 7.88(d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 5.22 (s, 2H), 4.81 (t, J= 12.4 Hz, 2H), 4.35 (t, J = 12.4 Hz, 2H). Calculated (M + H): 465.01,Found (M + H): 464.9, HPLC purity 99.68%. 334

5-(4-chloro-3- (trifluoromethyl)phenyl)- 3-(2-oxo-2-(2-(trifluoromethyl) pyrrolidin-1- yl)ethyl)thieno[2,3-d][1,2,3]triazin-4(3H)- one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.40 (s,1H), 8.07 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H),5.62- 5.18 (m, 3H), 4.69 (m, 1H), 3.75 (m, 2H), 2.22-1.92 (m, 3H).Calculated (M + H): 511.04, Found (M + H): 511.0, HPLC purity: 99.29%.

I. Preparation of Thienopyridazinones Example 335: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one

Step 1:

Preparation of 4-bromo-2-formylthiophene-3-carboxylic acid

To a mixture of diisopropylamine (4.58 mL, 32.60 mmol) intetrahydrofuran (20 mL) was added n-butyl lithium (1.6 M in hexane)(24.1 mL, 36.22 mmol) at −30° C. and stirred for 45 min at −10° C. to−30° C. The reaction mixture was allowed cool to −78° C., added slowly amixture of 4-bromothiophene-3-carboxylic acid (3.0 g, 14.49 mmol) andhexamethylphosphoramide (0.25 g, 1.45 mmol) in tetrahydrofuran andstirred for 1 h at −78° C. After 1 h, dimethylformamide was added slowlyto above reaction mixture at −78° C. The mixture was gradually allowedto warm to room temperature and stirred for 1 h. The reaction wasquenched with water (100 mL), acidified with 5M hydrochloric acid andfiltered through celite, the filtrate was extracted with dichloromethane(3×250 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford crude product.The crude product was purified by silica gel (60-120) columnchromatography using 4% methanol in dichloromethane to obtain titlecompound 4-bromo-2-formylthiophene-3-carboxylic acid (2.8 g, 76% LCMSpurity) as a red gummy. Calculated (M+H): 234.90; Found (M+H): 235.0.

Step 2:

Preparation of ethyl 4-bromo-2-formylthiophene-3-carboxylate

To a stirred mixture of 4-bromo-2-formylthiophene-3-carboxylic acid (2.8g, 11.91 mmol) (crude), potassium carbonate (4.1 g, 29.79 mmol) indimethylformamide was added ethyl iodide at room temperature. Theresulting mixture was heated to 55° C. and stirred for 5 h. The reactionmixture was allowed to cool to room temperature, diluted with water (100mL) and extracted with ethyl acetate (3×250 mL). The combined organiclayers were washed with water, brine solution, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to afford crudeproduct which was purified by silica gel (60-120) column chromatographyusing 10% ethyl acetate in hexane to obtain title compound ethyl4-bromo-2-formylthiophene-3-carboxylate (1.7 g) as pale yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ (ppm) 10.28 (s, 1H), 7.64 (s, 1H), 4.50-4.45(m, 2H), 1.44 (t, J=6.8 Hz, 3H).

Step 3:

Preparation of 3-bromothieno[2,3-d]pyridazin-4(5H)-one

To a solution of ethyl 4-bromo-2-formylthiophene-3-carboxylate (1.56 g,5.93 mmol) in ethanol (10 mL) was added hydrazine solution (1M intetrahydrofuran solution). The reaction mixture was heated to 80° C. andstirred for 2 h. The mixture was allowed to cool to room temperature,the precipitated product was filtered, washed with dichloromethane anddried to obtain title compound 3-bromothieno[2,3-d]pyridazin-4(5H)-one(0.81 g, 59% yield) as a white solid. Calculated (M+H): 230.91; Found(M+H): 230.9.

Step 4:

Preparation of3-bromo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one

To a mixture of 3-bromothieno[2,3-d]pyridazin-4(5H)-one (0.2 g, 0.87mmol) and potassium carbonate (0.29 g, 2.16 mmol) in dry acetone wasadded 2-chloro-1-(pyrrolidin-1-yl)ethanone (0.15 g, 1.04 mmol). Theresulting mixture was heated to 55° C. and stirred for 5 h. The reactionmixture was allowed to cool to room temperature, filtered the solid, andwashed with ethyl acetate. The filtrate was concentrated under vacuum toafford crude product, which was purified by silica gel (60-120) columnchromatography using 5% methanol in dichloromethane to afford the titlecompound3-bromo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one(0.23 g, 79.3% yield) as a white solid. Calculated (M+H): 341.98; Found(M+H): 341.9.

Step 5:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one

A mixture of3-bromo-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one(0.075 g, 0.22 mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronicacid (0.049 g, 0.22 mmol) in a mixture of 1,4-dioxane (5 mL) and water(2 mL) was purged with argon for 10 min. Then Pd(dppf)Cl₂.DCM (0.017 g,0.02 mmol) and potassium carbonate (0.09 g, 066 mmol) was added underargon and mixture was heated to 100° C. and stirred for 2 h. The mixturewas allowed to cool to room temperature, filtered through celite pad andthoroughly washed with ethyl acetate. The filtrate was washed withwater, brine, dried over sodium sulfate, concentrated under vacuum toafford the crude compound, which was purified by silica gel (60-120)column chromatography using 5% methanol in dichloromethane to afford thetitle compound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one(0.068 g, 70.8%, yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.64 (s,1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 4.90 (s, 2H), 3.48 (t, J=6.8 Hz, 2H), 3.27 (t, J=6.8 Hz, 2H),1.90-1.85 (m, 2H), 1.78-1.73 (m, 2H). Calculated (M+H): 442.05; Found(M+1): 442.0, HPLC purity 97.6%.

TABLE 35 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical data 336

3-(4-chloro-3- fluorophenyl)-5-(2- oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3- d]pyridazin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.62 (s, 1H), 8.13 (s, 1H), 7.61-7.55 (m, 2H), 7.37 (d, J = 7.6Hz, 1H), 4.89 (s, 2H), 3.48 (t, J = 6.8 Hz, 2H), 3.24 (t, J = 6.8 Hz,2H), 2.04-1.87 (m, 2H), 1.78-1.74 (m, 2H). Calculated (M + H): 392.06,Found (M + H): 392.0, HPLC purity 99.27%. 337

3-(3-chloro-4- fluorophenyl)-5-(2- oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3- d]pyridazin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.61 (s, 1H), 8.09 (s, 1H), 7.32 (d, J = 6.4 Hz, 1H), 7.50 (brs,1H), 7.44-7.00 (m, 1H), 4.89 (s, 2H), 3.48 (t, J = 6.8 Hz, 2H), 3.26 (t,J = 6.8 Hz, 2H), 1.91-1.87 (m, 2H), 1.77-1.73 (m, 2H). Calculated (M +H): 392.06, Found (M + H): 392.0, HPLC purity 99.14%. 338

3-(3,4- dichlorophenyl)-5-(2- oxo-2-(pyrrolidin-1- yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one ¹H NMR (400 MHz, DMSO- d6) δ (ppm); 8.62 (s, 1H),8.14 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.77(dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 4.90 (s, 2 H), 3.48 (t, J = 6.8 Hz,2H), 3.27 (t, J = 6.8 Hz, 2H), 1.92-1.86 (m, 2H), 1.78-1.72 (m, 2H).Calculated (M + H): 408.03, Found (M + H): 408.0; HPLC purity 99.51%.

Example 339: Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyridazin-4(5H)-one

Step 1:

Preparation of ethyl 2-(3-bromo-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetate

To a mixture of 3-bromothieno[2,3-d]pyridazin-4(5H)-one (0.65 g, 2.81mmol) and potassium carbonate (1.16 g, 8.44 mmol) in dry acetone wasadded ethyl 2-bromoacetate (0.62 mL, 5.63 mmol). The resulting mixturewas heated to 55° C. and stirred for 5 h. The reaction mixture wasallowed to cool to room temperature, filtered the solid, and washed withethyl acetate. The filtrate was concentrated under vacuum to affordcrude product, which was purified by silica gel (60-120) columnchromatography using 30% ethyl acetate in hexane to afford the titlecompound ethyl 2-(3-bromo-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetate(0.78 g, 87% yield) as a white solid. Calculated (M+H): 316.95, Found(M+H): 316.9.

Step 2:

Preparation of 2-(3-bromo-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)aceticacid

To a suspension of ethyl2-(3-bromo-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetate (0.68 g, 2.14mmol) in a mixture of tetrahydrofuran and water (10 mL: 10 mL) was addedlithium hydroxide mono hydrate (0.27 g, 6.43 mmol) at 0° C. Theresulting suspension was gradually allowed to warm to room temperatureand stirred for 3 h. The reaction mixture was allowed to cool to 0° C.and acidified with 1.5M hydrochloric acid solution to pH 2 to 3, theprecipitated product was filtered and dried to obtain the title compound2-(3-bromo-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetic acid (0.58 g, 93%yield) as a colorless solid. Calculated (M+H): 288.9, Found (M+H):288.9.

Step 3:

Preparation of3-bromo-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyridazin-4(5H)-one

To a solution of 2-(3-bromo-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)aceticacid (0.3 g, 1.08 mmol) in dichloromethane (20 mL) was added3,3-difluoroazetidine hydrochloride (0.13 g, 1.04 mmol) andtriethylamine (1.16 mL, 8.30 mmol). The reaction mixture was allowed tocool to 0° C. and 1-propanephosphonic anhydride (50% solution in ethylacetate) (1.31 mL, 2.07 mmol) was added, the mixture was allowed to warmto room temperature and stirred for 16 h. The reaction mixture wasdiluted with dichloromethane (100 mL), washed with water (2×50 mL),brine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford crude product, which was purified by silica gel(60-120) column chromatography using 5% methanol in dichloromethane aseluent to afford the title compound3-bromo-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyridazin-4(5H)-one(0.34 g, 90% yield) as off white solid. Calculated (M+H): 363.95, Found(M+1): 363.9.

Step 4:

Preparation of3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyridazin-4(5H)-one

To a stirred solution of3-bromo-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyridazin-4(5H)-one(0.075 g, 0.21 mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronicacid (0.046 g, 0.21 mmol) in a mixture of 1,4-dioxane (5 mL) and water(2 mL) and the mixture was purged with argon for 10 min. ThenPd(dppf)Cl₂.DCM (0.008 g, 0.010 mmol) and potassium carbonate (0.08 g,0.62 mmol) was added under argon atmosphere. The reaction mixture washeated to 100° C. and stirred for 2 h. The reaction mixture was allowedto cool to room temperature, filtered through celite pad and washed withethyl acetate. The filtrate was washed with water, brine, dried overanhydrous sodium sulfate, concentrated to afford the crude compound,which was purified by silica gel (60-120) column chromatography using 5%methanol in dichloromethane to afford the title compound3-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyridazin-4(5H)-one(0.052 g, 54.7%, yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.66 (s, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.81 (d, J=7.6 Hz, 1H),7.74 (d, J=8.4 Hz, 1H), 4.87 (s, 2H), 4.72 (t, J=12 Hz, 2H), 4.30 (t,J=12 Hz, 2H). Calculated (M+H): 464.02; Found (M+1): 464.0, HPLC purity99.7%.

TABLE 36 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical data 340

3-(4-chloro-3- fluorophenyl)-5-(2- (3,3-difluoroazetidin- 1-yl)-2-oxoethyl)thieno[2,3- d]pyridazin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.65 (s, 1H), 8.14 (s, 1H), 7.61-7.56(m, 2H), 7.38 (d, J = 8.4Hz, 1H), 4.87 (s, 2H), 4.71 (t, J = 12.4 Hz, 2H), 4.31 (t, J = 12.4 Hz,2H), Calculated (M + H): 414.02, Found (M + H): 414.0, HPLC purity99.7%. 341

3-(3-chloro-4- fluorophenyl)-5-(2- (3,3-difluoroazetidin- 1-yl)-2-oxoethyl)thieno[2,3- d]pyridazin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.64 (s, 1H), 8.11 (s, 1H), 7.73 (d, J = 6.0 Hz, 1H), 7.50 (brs,1H), 7.44-7.40 (m, 1H), 4.87 (s, 2 H), 4.72 (brs, 2H), 4.3 (brs, 2H);Calculated (M + H): 414.02, Found (M + H): 414.0, HPLC purity 99.3%. 342

3-(4-chloro-3- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[2,3- d]pyridazin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆)δ (ppm); 8.63 (s, 1H), 8.13 (s, 1H), 7.61-7.56 (m, 2H), 7.38 (d, J = 8.0Hz, 1H), 5.47- 5.23 (m, 1H), 5.02-4.84 (m, 2H), 3.90-3.39 (m, 4H), 2.23-2.06 (m, 2H); Calculated (M + H): 410.05, Found (M + H): 410.3, HPLCpurity 99.21%. 343

3-(3-chloro-4- fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[2,3- d]pyridazin-4(5H)-one ¹H NMR (400 MHz, DMSO- d₆)δ (ppm); 8.63 (s, 1H), 8.10 (s, 1H), 7.74-7.71 (dd, J = 2.8 Hz, J = 7.2Hz, 1H), 7.53-7.49 (m, 1H), 7.44-7.40 (m, 1H), 5.47-5.23 (m, 1H),5.02-4.84 (m, 2H), 3.90-3.35 (m, 4H), 2.22-2.05 (m, 2H). Calculated (M +H): 410.05, Found (M + H): 410.3, HPLC purity 99.82%. 344

3-(4-chloro-3- (trifluoromethyl) phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)thieno[2,3- d]pyridazin-4(5H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm); 8.65 (s, 1H), 8.21 (s, 1H), 7.97 (s,1H), 7.81(d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 5.47-5.22 (m,1H), 5.03-4.84 (m, 2H), 3.90-3.38 (m, 4H), 2.22-2.05 (m, 2H). Calculated(M + H): 460.04, Found (M + H): 460.0, HPLC purity 99.42%.

J. Preparation of Isothienopyrimidinones Example 345: Preparation of5-(4-chlorophenyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,4-d]pyrimidin-4(3H)-one

Step-1:

Preparation of (E)-methyl4-chloro-2-(4-chlorobenzylidene)-3-oxobutanoate

To a stirred solution of 1-(4-chlorophenyl)ethanone (10.0 g, 71.13 mmol)and methyl 4-chloro-3-oxobutanoate (8.2 mL, 71.13 mmol) in toluene (200mL) was added morpholine (0.3 mL, 3.55 mmol) and acetic acid (0.22 mL,3.91 mmol) at room temperature and the mixture was heated to 150° C.with azeotropic removal of water using Dean-stark apparatus for 5 h. Thereaction mixture was cooled room temperature, diluted with ethyl acetate(200 mL), washed with water (100 mL), brine (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the crude product, which was purified by silica gel columnchromatography using 10% ethyl acetate in hexane to obtain the titlecompound (E)-methyl 4-chloro-2-(4-chlorobenzylidene)-3-oxobutanoate (9.0g, 47% yield) as white solid. Calculated (M+H): 273.0, found (M+H):273.0.

Step-2:

Preparation of methyl2-(4-chlorophenyl)-4-oxotetrahydrothiophene-3-carboxylate

To a stirred solution of (E)-methyl4-chloro-2-(4-chlorobenzylidene)-3-oxobutanoate (8.0 g, 29.41 mmol) inmethanol (100 mL) was added sodium sulfide (8.34 g, 58.82 mmol) at roomtemperature and stirred for 1 h. The reaction mixture was poured on tocold 1N hydrochloric acid solution (250 mL) and extracted withdichloromethane (3×100 mL). The combined organic extract was washed withbrine (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to afford the crude product, which waspurified by silica gel column chromatography using 15% ethyl acetate inhexane to obtain the title compound methyl2-(4-chlorophenyl)-4-oxotetrahydrothiophene-3-carboxylate (5.8 g, 73.0%yield) as brown solid. Calculated (M−H): 269.01, found (M−H): 269.0.

Step-3:

Preparation of methyl 4-amino-2-(4-chlorophenyl)thiophene-3-carboxylate

To a stirred solution of methyl2-(4-chlorophenyl)-4-oxotetrahydrothiophene-3-carboxylate (5.8 g, 21.48mmol) in methanol: acetonitrile mixture (100 mL, 7:3) was addedhydroxylamine hydrochloride (1.86 g, 26.85 mmol) at room temperature andthe reaction mixture was heated to 80° C. for 5 h. The reaction mixturewas cooled to room temperature and poured on to saturated sodiumbicarbonate solution (100 mL) and extracted with ethyl acetate (3×50mL). The combined organic layer was washed with brine (50 mL), driedover anhydrous sodium sulfate and concentrated under vacuum to affordthe crude product, which was purified by silica gel columnchromatography using 12% ethyl acetate in hexane to obtain the titlecompound methyl 4-amino-2-(4-chlorophenyl)thiophene-3-carboxylate (3.0g, 55% yield) as off white solid. Calculated (M+H): 268.0, found (M+H):268.0.

Step-4:

Preparation of 5-(4-chlorophenyl)thieno[3,4-d]pyrimidin-4(3H)-one

A solution of methyl 4-amino-2-(4-chlorophenyl)thiophene-3-carboxylate(3.0 g, 11.23 mmol) in formamide (25 mL) was heated at 180° C. for 15 h.The reaction mixture was poured on to ice-water (100 mL), theprecipitated product was filtered, washed with water (100 mL) and driedto obtain the title compound5-(4-chloro-phenyl)thieno[3,4-d]pyrimidin-4(3H)-one (3.0 g, crude) asoff white solid. Calculated (M+H): 263.0, Found (M+H): 263.0.

Step-5:

Preparation of ethyl2-(5-(4-chlorophenyl)-4-oxothieno[3,4-d]pyrimidin-3(4H)-yl)acetate

To a stirred solution of5-(4-chloro-3-fluorophenyl)thieno[3,4-d]pyrimidin-4(3H)-one (1.5 g, 5.7mmol) and ethyl-2-bromoacetate (1.26 mL, 11.42 mmol) in acetone (50 mL)was added potassium carbonate (2.36 g, 17.12 mmol) and the mixture washeated to 55° C. for 15 h. The reaction mixture was filtered through thecelite and the filtrate was evaporated. The crude material was purifiedby silica gel column chromatography using 40% ethyl acetate in hexane toobtain the title compound ethyl2-(5-(4-chlorophenyl)-4-oxothieno[3,4-d]pyrimidin-3(4H)-yl)acetate (1.5g, 75% yield) as gummy material. Calculated (M+H): 349.03, Found (M+H):349.0.

Step-6:

Preparation of2-(5-(4-chlorophenyl)-4-oxothieno[3,4-d]pyrimidin-3(4H)-yl)acetic acid

To a stirred solution of ethyl2-(5-(4-chlorophenyl)-4-oxothieno[3,4-d]pyrimidin-3(4H)-yl)acetate (1.5g, 4.3 mmol) in tetrahydrofuran:water mixture (20 mL, 1:1) was addedlithium hydroxide monohydrate (0.9 g, 21.5 mmol) at 0° C. and thereaction mixture was stirred at room temperature for 1 h. Aftercompletion of the reaction, mixture was concentrated, the residue wasdiluted with water (50 mL) and acidified with 1.5 N hydrochloric acidsolution to pH˜2. The precipitated solid was filtered, washed with water(50 mL) and dried to obtain the title compound2-(5-(4-chlorophenyl)-4-oxothieno[3,4-d]pyrimidin-3(4H)-yl)acetic acid(1.1 g, crude) as off white solid. Calculated (M+H): 321, found (M+H):321.0.

Step-7:

Preparation of5-(4-chlorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one

To a stirred solution of2-(5-(4-chlorophenyl)-4-oxothieno[3,4-d]pyrimidin-3(4H)-yl)acetic acid(0.1 g, 0.31 mmol) in dichloromethane (10 mL) was added triethylamine(0.26 mL, 1.87 mmol) and pyrrolidine (0.051 mL, 0.62 mmol) at roomtemperature and the reaction mixture was cooled to 0° C. Then1-propanephosphonic anhydride (T₃P) (0.3 mL, 0.46 mmol, 50% solution inethyl acetate) was added dropwise and the reaction mixture was stirredat room temperature for 15 h. The reaction mixture was quenched withwater (25 mL) and extracted with dichloromethane (3×25 mL). The combinedorganic layer was washed with brine (25 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford the crudeproduct, which was purified by silica gel column chromatography using 4%methanol in dichloromethane to obtain the title compound5-(4-chlorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one(0.075 g, 65% yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.93 (s, 1H), 7.87 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.5 (d, J=8.4Hz, 2H), 4.68 (s, 2H), 3.47 (t, J=7.2 Hz, 2H), 3.30 (brs, 2H), 1.94-1.89(m, 2H), 1.81-1.76 (m, 2H). Calculated (M+H): 374.07, Found (M+H):374.1. HPLC Purity: 99.34%.

TABLE 37 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 346

2-(5-(4-chlorophenyl)-4- oxothieno[3,4- d]pyrimidin-3(4H)-yl)-N-cyclopropylacetamide ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 8.26 (brs,1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.51 (d, J =7.6 Hz, 2H), 4.43 (s, 2H), 2.66- 2.61 (m, 1H), 0.6 (d, J = 6.4 Hz, 2H),0.39 (brs, 2H). Calculated (M + H): 360.05, Found (M + H): 360.1, HPLCpurity: 99.06%. 347

2-(5-(4-chlorophenyl)-4- oxothieno[3,4- d]pyrimidin-3(4H)-yl)-N-cyclobutylacetamide ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 8.26 (d, J =6.8 Hz, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.50(d, J = 8.4 Hz, 2H), 4.45 (s, 2H), 4.19-4.13 (m, 1H), 2.13-2.11 (m, 2H),1.90- 1.85 (m, 2H), 1.63-1.55 (m, 2H). Calculated (M + H): 374.07, Found(M + H): 374.1, HPLC purity: 99.44%. 348

5-(4-chlorophenyl)-3-(2- (3,3-difluoroazetidin-1- yl)-2-oxoethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.94 (s, 1H), 7.89 (s, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.51 (d, J= 8.0 Hz, 2H), 4.73 (t, J = 11.2 Hz, 2H), 4.63 (s, 2H), 4.35 (t, J =11.6 Hz, 2H). Calculated (M + H): 396.03, Found (M + H): 396.0, HPLCpurity: 98.56%. 349

3-(2-(azetidin-1-yl)-2- oxoethyl)-5-(4- chlorophenyl)thieno[3,4-d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 7.94 (s, 1H),7.87 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.49(s, 2H), 4.21 (t, J = 7.6 Hz, 2H), 3.87 (t, J = 7.6 Hz, 2H), 2.31-2.22(m, 2H). Calculated (M + H): 360.05, Found (M + H): 360.1; HPLC purity:99.46%. 350

5-(4-chlorophenyl)-3-(2- oxo-2-(piperidin-1- yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 7.93 (s, 1H),7.87 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.5 (d, J = 8.4 Hz, 2H), 4.77(s, 2H), 3.44-3.28 (m, 4H), 1.57 (brs, 4H), 1.42 (brs, 2H). Calculated(M + H): 388.1, Found (M + H): 388.1, HPLC purity: 99.74%. 351

5-(4-chlorophenyl)-3-(2- (3-methoxyazetidin-1- yl)-2-oxoethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.94 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 4.53 (s, 2H), 4.41-4.37(m, 1H), 4.25- 4.24 (m, 1H),4.07-4.03 (m, 2H), 3.69-3.66 (m, 1H), 3.21 (s, 3H). Calculated (M + H):390.06, Found (M + H): 390.1; HPLC purity: 99.52%. 352

5-(4-chlorophenyl)-3-(2- (3-hydroxypyrrolidin-1- yl)-2-oxoethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, CDCl₃) δ(ppm): 7.75 (d, J = 3.2 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.54 (s, 1H),7.39 (d, J = 8.4 Hz, 2H), 4.76-4.45 (m, 3H), 3.78-3.51 (m, 5H),2.10-1.97 (m, 2H). Calculated (M + H): 390.06, Found (M + H): 390.1,HPLC purity: 99.85%. 353

5-(4-chlorophenyl)-3-(2- (4,4-difluoropiperidin-1- yl)-2-oxoethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.92 (s, 1H), 7.88 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.50 (d, J= 8.4 Hz, 2H), 4.86 (s, 2H), 3.61 (brs, 2H), 3.55 (brs, 2H) 2.09-1.92(m, 4H). Calculated (M + H): 424.06, Found (M + H): 424.1, HPLC purity:99.70%. 354

5-(4-chlorophenyl)-3-(2- morpholino-2- oxoethyl)thieno[3,4-d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 7.93 (s, 1H),7.87 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.5 (d, J = 8.4 Hz, 2H), 4.81(s, 2H), 3.63 (brs, 2H), 3.56 (brs, 2H), 3.52 (brs, 2H), 3.42 (brs, 2H).Calculated (M + H): 390.06, Found (M + H): 390.4, HPLC purity: 99.4%.355

5-(4-chlorophenyl)-3-(2- oxo-2-(2- (trifluoromethyl)pyrrolidin-1-yl)ethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆)δ (ppm): 7.96-7.94 (m, 1H), 7.89 (s, 1H), 7.67-7.65 (m, 2H), 7.51-7.49(m, 2H), 4.81 (s, 2H), 4.75-4.71 (m, 1H), 3.67 (brs, 2H), 2.15-1.90 (m,4H). Calculated (M + H): 442.85; Found (M + H): 442.2, HPLC purity:99.45%. 356

3-(2-oxo-2-(pyrrolidin- 1-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)thieno[3,4-d]pyrimidin- 4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm):7.96 (brs, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 4.69(s, 2H), 3.48 (t, J = 6.4 Hz, 2H), 3.28 (brs, 2H), 1.93-1.89 (m, 2H),1.80-1.75 (m, 2H). Calculated (M + H): 408.41, Found (M + H): 408.0,HPLC purity: 99.28%. 357

3-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin- 1-yl)ethyl)-5-(4-(trifluoromethyl)phenyl) thieno[3,4-d]pyrimidin- 4(3H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm): 7.98 (brs, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.80(d, J = 8.0 Hz, 2H), 5.1-4.8 (m, 2H), 4.72-4.71 (m, 1H), 3.66 (brs, 2H),2.14-1.9 (m, 4H). Calculated (M + H): 476.08, Found (M + H): 476.1, HPLCpurity: 99.54%. 358

3-(2-(3,3- difluoroazetidin-1-yl)-2- oxoethyl)-5-(4-(trifluoromethyl)phenyl) thieno[3,4-d]pyrimidin- 4(3H)-one ¹H NMR (400MHz, DMSO- d₆) δ (ppm): 7.96 (s, 2H), 7.86- 7.84 (m, 2H), 7.80-7.78 (m,2H), 4.72 (t, J = 12 Hz, 2H), 4.63 (s, 2H), 4.33 (t, J = 12 Hz, 2H).Calculated (M + H): 414.02, Found (M + H): 392, HPLC purity: 99.51%. 359

5-(3-chloro-4- fluorophenyl)-3-(2-oxo- 2-(pyrrolidin-1-yl)ethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.92-7.88 (m, 3H), 7.61 (brs, 1H), 7.50-7.45 (m, 1H), 4.69 (s,2H), 3.48 (t, J = 7.2 Hz, 2H), 3.27 (brs, 2H), 1.92-1.89 (m, 2H),1.79-1.74 (m, 2H). Calculated (M + H): 392.06, Found (M + H): 392, HPLCPurity: 99.51%. 360

5-(3-chloro-4- fluorophenyl)-3-(2-(3,3- difluoroazetidin-1-yl)-2-oxoethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.93-7.87 (m, 3H), 7.63-7.60 (m, 1H), 7.50-7.46 (m, 1H), 4.72 (t,J = 12.4 Hz, 2H), 4.64 (s, 2H), 4.33 (t, J = 12.4 Hz, 2H). Calculated(M + H): 414.8, Found (M + H): 414.0, HPLC Purity: 98.27%. 361

5-(4-chloro-3- (trifluoromethyl)phenyl)- 3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4- d]pyrimidin-4(3H)-one 1H NMR (400 MHz, DMSO- d₆)δ (ppm): 8.10 (s, 1H), 7.94- 7.89 (m, 3H), 7.79-7.77 (m, 1H), 4.69 (s,2H), 3.47 (brs, 2H), 3.26 (brs, 2H) 1.91 (brs, 2H), 1.77 (brs, 2H).Calculated (M + H): 442.05, Found (M + H): 442.3, HPLC purity: 99.69%.362

5-(4-chloro-3- (trifluoromethyl)phenyl)- 3-(2-(3,3-difluoroazetidin-1-yl)-2- oxoethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹HNMR (400 MHz, DMSO- d₆) δ (ppm): 8.13 (s, 1H), 7.97- 7.95 (m, 2H), 7.90(d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 4.72 (t, J = 12 Hz, 2H),4.65 (s, 2H), 4.32 (t, J = 12 Hz, 2H). Calculated (M + H): 464.02, Found(M + H): 464.3, HPLC purity: 99.80%. 363

5-(4-chloro-3- fluorophenyl)-3-(2-(3,3- difluoroazetidin-1-yl)-2-oxoethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.94 (s, 1H), 7.93 (s, 1H), 7.74-7.72 (m, 1H), 7.65 (t, J = 8.0Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 4.72 (t, J = 12 Hz, 2H), 4.63 (s,2H), 4.33 (t, J = 12.4 Hz, 2H). Calculated (M + H): 414.2, Found (M +H): 414.0, HPLC purity: 99.72%. 364

5-(4-chloro-3- fluorophenyl)-3-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.95 (s, 1H), 7.92 (s, 1H), 7.73 (d, J = 10.0 Hz, 1H), 7.66-7.62(m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 5.49-5.24 (m, 1H), 4.82-4.64 (m, 2H), 3.87-3.36 (m, 4H), 2.25-2.07 (m, 2H). Calculated (M + H): 410.04,Found (M + H): 410.0, HPLC purity: 96.50%. 365

5-(4-chloro-3- fluorophenyl)-3-(2-oxo- 2-(3-(trifluoromethyl)pyrrolidin- 1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 7.97-7.93 (m,2H), 7.74-7.71 (m, 1H), 7.67-7.63 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H),5.03-4.69 (m, 2H), 3.65 (s, 2H), 2.13-1.91(m, 5H). Calculated (M + H):360.04; Found (M + H): 460.0, HPLC purity: 99.95%.

Example 366:5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one

A mixture of7-bromo-5-(4-chloro-3-fluorophenyl)thienopyrimidin-4(3H)-one (0.08 g,0.24 mmol), 2-chloro-1-(pyrrolidin-1-yl)ethanone (0.071 g, 0.48 mmol)and potassium carbonate (0.11 g, 0.85 mmol) in acetone (10 mL) washeated at 55° C. for 5 h. The reaction mixture was filtered and thefiltrate was concentrated. The crude was purified by silica gel columnchromatography using 4% methanol in dichloromethane to afford the titlecompound5-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one(0.02 g, 20% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.10 (s, 1H), 7.94-7.89 (m, 3H), 7.79-7.77 (m, 1H), 4.69 (s, 2H), 3.47(brs, 2H), 3.26 (brs, 2H) 1.91 (brs, 2H), 1.77 (brs, 2H). Calculated(M+H): 442.05, Found (M+H): 442.3. HPLC purity: 99.69%.

TABLE 38 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 367

5-(4-chloro-3- fluorophenyl)-3-(2-oxo- 2-(pyrrolidin-1-yl)ethyl)thieno[3,4- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 7.93 (s, 1H), 7.91 (s, 1H), 7.75-7.71 (dd, J = 2.4 Hz, J = 2.0Hz, 2H), 7.66-7.62 (m, 1H), 7.49-7.46 (m, 1H), 4.69 (s, 2H), 3.48 (t, J= 6.8 Hz, 2H), 3.27 (brs, 1H), 1.94- 1.87 (m, 2H), 1.79-1.73 (m, 2H).Calculated (M + H): 392.06; Found (M + H): 392.0, HPLC purity: 99.68%.

Examples 368 and 369: Preparation of5-(4-chloro-3-fluorophenyl)-7-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one

Step-1:

Preparation of7-bromo-5-(4-chloro-3-fluorophenyl)thieno[3,4-d]pyrimidin-4(3H)-one

To a solution of5-(4-chloro-3-fluorophenyl)thieno[3,4-d]pyrimidin-4(3H)-one (0.07 g,0.25 mmol) in tetrahydrofuran:acetic acid mixture (17.5 mL, 6:1), wasadded N-bromosuccinimide and the reaction mixture was stirred at roomtemperature for 15 min. The reaction mixture was concentrated and thecrude was purified by column chromatography using 80% ethyl acetate inhexane to afford the title compound7-bromo-5-(4-chloro-3-fluorophenyl)thieno[3,4-d]pyrimidin-4(3H)-one(0.065 crude). Calculated (M+H): 358.90, Found M+H: 358.9.

Step-2:

Preparation of7-bromo-5-(4-chloro-3-fluorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one

A mixture of7-bromo-5-(4-chloro-3-fluorophenyl)thieno[3,4-d]pyrimidin-4(3H)-one (0.9g, 2.50 mmol), 2-chloro-1-(pyrrolidin-1-yl)ethanone (0.738 g, 5.00 mmol)and potassium carbonate (1.037 g, 7.51 mmol) in acetone (40 mL) washeated at 60° C. for 4 h. The reaction mixture was filtered and thefiltrate was concentrated. The crude was purified by columnchromatography using 70% ethyl acetate in hexane to afford the titlecompound7-bromo-5-(4-chloro-3-fluorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one(0.65 g, 55% yield) as a brownish solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.05 (s, 1H), 7.74-7.71 (m, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.47 (d,J=7.2 Hz, 1H), 4.69 (s, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.29-3.27 (m, 2H),1.96-1.87 (m, 2H), 1.79-1.73 (m, 2H). Calculated (M+H): 469.97, FoundM+H: 469.9, HPLC purity: 99.07%.

Step-3:

Preparation of5-(4-chloro-3-fluorophenyl)-7-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one

To a solution of7-bromo-5-(4-chloro-3-fluorophenyl)-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one(0.25 g, 0.53 mmol) in dioxane (50 mL) potassium carbonate (0.367 g,2.66 mmol) was added and the reaction mixture was purged with argon for20 minutes. Then trimethylboroxine (0.074 ml, 0.53 mmol) andtetrakis(triphenylphosphine) palladium(0) (0.092 g, 0.08 mmol) wereadded and the reaction mixture was heated at 95° C. for 24 h. Thereaction mixture was filtered through celite and filtrate wasconcentrated. The crude was purified by column chromatography followedby preparative HPLC (analytical conditions: column: Inertsil ODS 3V (250mm×4.6 mm×50, mobile phase (A): 0.01% ammonia in water, mobile phase(B): methanol, flow rate: 1.0 mL/min, T/% B: 0/20, 8/80, 25/90, 27/20,30/20, wavelength: 220 nm) to afford the title compound5-(4-chloro-3-fluorophenyl)-7-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[3,4-d]pyrimidin-4(3H)-one(0.040 g, 18% yield) as a off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.90 (s, 1H), 7.72-7.68 (dd, J=2.4 Hz, J=10.8 Hz, 1H), 7.63-7.61(m, 1H), 7.45-7.43 (dd, J=1.2 Hz, =8.4 Hz, 1H), 4.68 (s, 2H), 3.48 (t,J=6.8 Hz, 2H), 3.29-3.25 (m, 2H), 2.62 (s, 3H), 1.92-1.87 (m, 2H),1.79-1.74 (m, 2H). Calculated (M+H): 406.07; Found (M+H): 406.0, HPLCpurity: 99.90%.

K. Preparation of Isopyrrolopyrimidinones Example 370: Preparation of3-(2-(azetidin-1-yl)-2-oxoethyl)-5-(4-chlorophenyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

Step 1:

Preparation of (E)-diethyl 2-((2-cyanovinyl)amino)malonate

To a mixture of isoxazole (5.0 g, 72.40 mmol) in ethanol (20 mL) wasadded a solution of sodium ethoxide in ethanol (21% in ethanol) (5.9 g,86.88 mmol) at 0° C. slowly (maintaining the temperature <8° C. whileaddition) and stirred for 45 min at 0° C. To the above reaction mixture,acetic acid (1.4 mL), diethyl 2-aminodimalonate hydrochloride (10.72 g,50.68 mmol), and sodium acetate (4.15 g, 50.68 mmol) were sequentiallyadded at 0° C., the mixture was allowed to warm to room temperature andstirred for 24 h. After completion of reaction, the reaction mixture wasconcentrated under reduced pressure, the residue was dissolved withdichloromethane (500 mL), washed with water, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to obtain title compound(E)-diethyl 2-((2-cyanovinyl)amino)malonate (10.2 g, crude) as orangegummy liquid, which was taken for next step without furtherpurification. Calculated (M+H): 227.10; Found (M+1): 227.1.

Step 2:

Preparation of ethyl 3-amino-1H-pyrrole-2-carboxylate

To a mixture of (E)-diethyl 2-((2-cyanovinyl)amino)malonate (10.2 gcrude, 45.09 mmol), in ethanol (25 mL) was added a solution of 21%sodium ethoxide in ethanol (22 mL) at room temperature. The resultingmixture was heated to reflux and stirred for 4 h. After 4 h, the mixturewas allowed to cool to room temperature and acetic acid (3 mL) wasadded. The solvent was removed under vacuum, the residue was dissolvedwith dichloromethane (500 mL), washed with an aqueous solution ofsaturated sodium bicarbonate, water, and brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to afford thecrude product. The crude material was purified by silica gel (60-120)column chromatography using 2.5% methanol in dichloromethane to affordethyl 3-amino-1H-pyrrole-2-carboxylate (2.0 g, impure) as a yellowsolid. Calculated (M+H): 155.07; Found (M+1): 155.1.

Step 3:

Preparation of ethyl 3-acetamido-1H-pyrrole-2-carboxylate

To a mixture of ethyl 3-amino-1H-pyrrole-2-carboxylate (2.0 g, 12.97mmol) and triethyl amine (5.4 mL, 38.92 mmol) in dichloromethane (100mL) was added acetyl chloride (1.1 mL, 15.57 mmol) at 0° C. The reactionmixture was allowed to warm to room temperature and stirred for 18 h.The progress of the reaction was monitored by TLC. The reaction mixturewas diluted with dichloromethane (100 mL), washed with a saturatedaqueous solution of sodium bicarbonate, water, and brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the crude product. The crude product was purified by silica gel(60-120) column chromatography using 3% methanol in dichloromethane toafford ethyl 3-acetamido-1H-pyrrole-2-carboxylate (2.08 g, 83.2% yield)as a yellow solid. Calculated (M+H): 197.08; Found (M+1): 197.1.

Step 4:

Preparation of ethyl3-acetamido-1-(4-chlorophenyl)-1H-pyrrole-2-carboxylate

To a mixture of ethyl 3-acetamido-1H-pyrrole-2-carboxylate (2.0 g, 10.19mmol) in dichloromethane (100 mL) was added triethylamine (6.4 mL, 45.87mmol), (4-chlorophenyl)boronic acid (3.18 g, 20.39 mmol), 4 Å molecularsieves (20 g) and copper(II)acetate (3.7 g, 20.39 mmol), at roomtemperature. The resulting mixture was stirred at room temperature inthe presence of air for 5 h. The progress of the reaction was monitoredby TLC. The reaction mixture was filtered and washed withdichloromethane. The filtrate was washed with 1M aqueous hydrochloricacid (100 mL×2) and the organic layer was dried over anhydrous sodiumsulfate, filtered, concentrated under vacuum to afford the crudeproduct. The crude material was purified by silica gel (60-120) columnchromatography using 30% ethyl acetate in hexane to afford ethyl3-acetamido-1-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (2.9 g, 93%yield) as orange yellow solid. Calculated (M+H): 307.08; Found (M+1):307.1.

Step 5:

Preparation of ethyl 3-amino-1-(4-chlorophenyl)-1H-pyrrole-2-carboxylate

To a solution of ethyl3-acetamido-1-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (2.9 g, 9.454mmol) in ethanol (100 mL) was added concentrated hydrochloric acid (10mL) at room temperature. The resulting mixture was heated to reflux andstirred for 3 h. After 3 h, the mixture was allowed to cool to roomtemperature and the solvent was removed under vacuum. The residue wasdissolved with ethyl acetate, washed with aqueous solution of saturatedsodium bicarbonate, water, brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford the title compoundethyl 3-amino-1-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (4.7 g, crude)as a pale brown solid, which was taken for next step without furtherpurification. Calculated (M+H): 265.07; Found (M+1): 265.1.

Step 6:

Preparation of 5-(4-chlorophenyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

A mixture of 3-amino-1-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (4.7 g,17.79 mmol) and formamide (40 mL) was heated to 180° C. and stirred for16 h. The reaction was monitored by TLC. The mixture was allowed to coolto room temperature and diluted with water (150 mL), the precipitatedsolid was filtered, washed with water, dried under vacuum to afford thetitle compound 5-(4-chlorophenyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one(4.0 g, 91.4% yield) as a brown solid. Calculated (M+H): 246.04; Found(M+H): 246.1.

Step 7:

Preparation of ethyl2-(5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)acetate

To a mixture of 5-(4-chlorophenyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one(2.0 g, 8.14 mmol) and potassium carbonate (3.37 g, 24.42 mmol) in dryacetone was added ethyl 2-bromoacetate (1.81 mL, 16.28 mmol). Theresulting mixture was heated to 55° C. and stirred for 5 h. The mixturewas allowed to cool to room temperature, filtered the solid, and washedwith ethyl acetate. The filtrate was concentrated under vacuum to affordcrude product, which was purified by silica gel (60-120) columnchromatography using 25% ethyl acetate in hexane to afford the titlecompound ethyl2-(5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)acetate(2.3 g, 85% yield) as an orange gummy compound. Calculated (M+H):332.07; Found (M+H): 332.1.

Step 8:

Preparation of2-(5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)aceticacid

To a suspension of ethyl2-(5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)acetate(2.3 g, 6.93 mmol) in a mixture of tetrahydrofuran and water (25 mL: 25mL) was added lithium hydroxide monohydrate (1.45 g, 34.66 mmol) at 0°C. The resulting suspension was gradually allowed to warm to roomtemperature and stirred for 2 h. After 2 h, the reaction mixture wasallowed to cool to 0° C. and acidified with 1.5M hydrochloric acidsolution to pH 2 to 3, the precipitated solid was filtered, washed withwater, dried under vacuum to afford the title compound2-(5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)aceticacid (1.7 g, 80% yield) as a colorless solid. Calculated (M+H): 304.04;Found (M+H): 304.1.

Step 9:

Preparation of3-(2-(azetidin-1-yl)-2-oxoethyl)-5-(4-chlorophenyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

To a solution of2-(5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-3-yl)aceticacid (0.1 g, 0.329 mmol) in dichloromethane (15 mL) was added azetidinehydrochloride (0.03 g, 0.033 mmol) and triethylamine (0.14 mL, 0.99mmol) at room temperature. The reaction mixture was allowed to cool to0° C. and 1-Propanephosphonic anhydride solution (50% solution in ethylacetate) (0.42 mL, 0.66 mmol) was added. The resulting mixture wasallowed to warm to room temperature and stirred for 16 h, aftercompletion of reaction, the reaction mixture was diluted withdichloromethane (25 mL), washed with water (2×25 mL), and brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford crude product. The crude product was purified bysilica gel (60-120) column chromatography using 3% methanol indichloromethane as eluent to afford the title compound3-(2-(azetidin-1-yl)-2-oxoethyl)-5-(4-chlorophenyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one(0.046 g, 42% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.08 (s, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.47 (d,J=8.8 Hz, 2H), 6.61 (d, J=2.4 Hz, 1H), 4.56 (s, 2H), 4.21 (t, J=7.6 Hz,2H), 3.86 (t, J=7.6 Hz, 2H), 2.25 (t, J=7.6 Hz, 2H). Calculated (M+H):343.09; Found (M+1): 343.3. HPLC purity: 98.12%.

TABLE 39 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical data 371

5-(4-chlorophenyl)-3- (2-morpholino-2- oxoethyl)-3H- pyrrolo[3,2-d]pyrimidin-4(5H)- one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm); 8.07 (s, 1H),7.69 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz,2H), 6.62 (d, J = 2.8 Hz, 1H), 4.88 (s, 2H), 3.63 (brs, 2H), 3.54 (brs,4H), 3.41 (brs, 2H). Calculated (M + H): 373.10; Found (M + 1): 373.1.HPLC purity 99.19%. 372

5-(4-chlorophenyl)-3- (2-(3- methoxyazetidin-1- yl)-2-oxoethyl)-3H-pyrrolo[3,2- d]pyrimidin-4(5H)- one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm);8.09 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.47(d, J = 8.8 Hz, 2H), 6.61 (d, J = 3.2 Hz, 1H), 4.60 (s, 2H), 4.41-4.37(m, 1H), 4.27-4.22 (m, 1H), 4.06-4.02 (m, 2H), 3.69-3.66 (m, 1H), 3.21(s, 3H). Calculated (M + H): 373.10; Found (M + 1): 373.1. HPLC purity99.34%. 373

5-(4-chlorophenyl)-3- (2-(4,4- difluoropiperidin-1- yl)-2-oxoethyl)-3H-pyrrolo[3,2- d]pyrimidin-4(5H)- one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm);8.07 (s, 1H), 7.69 (d, J = 3.2 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.47(d, J = 8.8 Hz, 2H), 6.62 (d, J = 2.8 Hz, 1H), 4.94 (s, 2H), 3.63 (brs,2H), 3.54 (brs, 2H), 2.09 (brs, 2H), 1.92 (brs, 2H). Calculated (M + H):407.10; Found (M + 1): 407.1. HPLC purity 99.37%. 374

5-(4-chlorophenyl)-3- (2-(3,3- difluoroazetidin-1-yl)- 2-oxoethyl)-3H-pyrrolo[3,2- d]pyrimidin-4(5H)- one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm);8.10 (s, 1H), 7.71 (d, J = 3.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.47(d, J = 8.8 Hz, 2H), 6.61 (d, J = 3.2 Hz, 1H), 4.76-4.70 (m, 4H), 4.33(t, J = 12.4 Hz, 2H). Calculated (M + H): 379.07; Found (M + 1): 379.4.HPLC purity 99.05%. 375

2-(5-(4-chlorophenyl)- 4-oxo-4,5-dihydro- 3H-pyrrolo[3,2-d]pyrimidin-3-yl)-N- cyclopropylacetamide ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 8.25 (d, J = 4 Hz, 1H), 8.10 (s, 1H), 7.68 (d, J = 3.2 Hz, 1H),7.53-7.46 (m, 4H), 6.61 (d, J = 2.8 Hz, 1H), 4.52 (s, 2H), 2.62-2.58 (m,1H), 0.60 (brs, 2H), 0.39 (brs, 2H). Calculated (M + H): 343.09, Found(M + H): 343.1. HPLC purity 99.39%. 376

5-(4-chlorophenyl)-3- (2-oxo-2-(pyrrolidin- 1-yl)ethyl)-3H- pyrrolo[3,2-d]pyrimidin-4(5H)- one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm); 8.08 (s, 1H),7.69 (d, J = 2.8 Hz, 1H), 7.53-7.46 (m, 4H), 6.62 (d, J = 3.2 Hz, 1H),4.76 (s, 2H), 3.5 (d, J = 6.8 Hz, 2H), 1.95-1.89 (m, 2H), 1.80-1.74 (m,2H). (Two protons are merged with DMSO water peak) Calculated (M + H):357.1, Found (M + H): 357.1. HPLC purity99.05%. 377

5-(4-chlorophenyl)-3- (2-oxo-2-(piperidin-1- yl)ethyl)-3H- pyrrolo[3,2-d]pyrimidin-4(5H)- one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm); 8.07 (s, 1H),7.68 (d, J = 3.2 Hz, 1H), 7.521 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.8Hz, 2H), 6.613 (d, J = 2.4 Hz, 1H), 4.86 (s, 2H), 3.45 (m, 2H), 3.39 (m,2H), 1.57 (m, 4H), 1.42 (m, 2H). Calculated M + H: 370.12; Found M + H:371.4; HPLC: 99.31% 378

2-(5-(4-chlorophenyl)- 4-oxo-4,5,6,7- tetrahydro-3H-pyrrolo[3,2-d]pyrimidin-3- yl)-N- cyclobutylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J = 7.2 Hz, 1H), 8.1 (s, 1H), 7.68 (s, 1H), 7.46- 7.53(m, 4H), 6.61 (s, 1H), 4.56 (s, 2H), 4.13-4.19 (m, 1H), 2.12-2.13 (m,2H), 1.88 (t, J = 9.1 Hz, 2H), 1.55-1.63 (m, 2H). Calculated M + H:190.94; Found M + H: 191.0; HPLC: 99.27% 379

5-(4-chlorophenyl)-3- (2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-yl)ethyl)-3H- pyrrolo[3,2- d]pyrimidin-4(5H)- one ¹H NMR(400 MHz, DMSO- d₆) δ (ppm); 8.09 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H),7.53-7.46 (m, 4H), 6.63 (d, J = 2.8 Hz, 1H), 5.04-4.79 (m, 2H), 4.70(brs, 1H), 3.67 (brs, 2H), 2.15- 1.90 (m, 4H). Calculated (M + H):425.09, Found (M + H): 425.1. HPLC purity 99.64%.

L. Preparation of Thiazolopyrimidinones Example 380: Preparation of3-(4-chlorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one

Step-1:

Preparation of 2-((4-chlorophenyl)(hydroxy)methylene)malononitrile

To a stirred solution of malononitrile (0.72 mL, 11.43 mmol) intetrahydrofuran (10 mL) was added sodium hydride (0.915 g, 22.85 mmol,60% in paraffin oil) portion-wise at 0° C. and the reaction mixture wasstirred at same temperature for 10 minutes. Then a solution of4-chlorobenzoyl chloride (2.0 g, 11.43 mmol) in tetrahydrofuran (10 mL)was added drop-wise and the reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was quenched with ice-water(25 mL), acidified with 1.5 N hydrochloric acid solution and extractedwith ethyl acetate (3×50 mL). The combined organic extract was washedwith brine (25 mL), dried over anhydrous sodium sulfate, filtered andevaporated. The crude material was washed with diethyl ether and driedto obtain the title compound2-((4-chlorophenyl)(hydroxy)methylene)malononitrile (2.5 g, crude) asoff white solid. Calculated (M−H): 203.01; Found (M−H): 203.1.

Step-2:

Preparation of 2-(chloro(4-chlorophenyl)methylene)malononitrile

To a stirred solution of2-((4-chlorophenyl)(hydroxy)methylene)malononitrile (1.0 g, 4.88 mmol)in phosphorous oxychloride (10 mL) was added triethylamine (0.68 mL,4.88 mmol) and the reaction mixture was heated at 100° C. for 1 h. Thereaction mixture was cooled and evaporated. The residue was quenchedwith ice-water (25 mL) and extracted with ethyl acetate (3×50 mL). Thecombined organic extract was washed with brine (25 mL), dried overanhydrous sodium sulfate, filtered and evaporated. The crude materialwas purified by silica gel column chromatography using 5% ethyl acetatein hexane to obtain the title compound2-(chloro(4-chlorophenyl)methylene)malononitrile (0.85 g, crude) asyellow solid. ¹H NMR (400 MHz, DMSO-do) δ (ppm): 7.58 (d, J=8.4 Hz, 2H),7.43 (d, J=8.4 Hz, 2H).

Step-3:

Preparation of 2-(amino(4-chlorophenyl)methylene)malononitrile

A solution of 2-(chloro(4-chlorophenyl)methylene)malononitrile (0.85 g,3.81 mmol) and ammonia in methanol (15 mL) was stirred at roomtemperature for 1 h. The reaction mixture was evaporated to dryness. Theresidue was washed with diethyl ether and dried to obtain the titlecompound 2-(amino(4-chlorophenyl)methylene)malononitrile (1.0 g, crude)as off white solid. Calculated (M−H): 202.03; Found (M−H): 202.

Step-4:

Preparation of (E)-3-amino-3-(4-chlorophenyl)-2-cyanoprop-2-enethioamide

To a stirred solution of 2-(amino(4-chlorophenyl)methylene)malononitrile(1.0 g, 4.91 mmol) in ethanol: water (12.5 mL, 4:1) mixture, was addeddiethyl dithiophosphate (1.24 mL, 7.36 mmol) and the reaction mixturewas heated at 90° C. for 15 h. The reaction mixture was evaporated todryness. The residue was washed with diethyl ether and dried to obtainthe title compound(E)-3-amino-3-(4-chlorophenyl)-2-cyanoprop-2-enethioamide (1.3 g, crude)as yellow solid. Calculated (M+H): 238.01; Found (M+H): 238.

Step-5:

Preparation of 5-amino-3-(4-chlorophenyl)isothiazole-4-carbonitrile

To a stirred solution of(E)-3-amino-3-(4-chlorophenyl)-2-cyanoprop-2-enethioamide (0.9 g, 3.78mmol) in methanol (20 mL) was added hydrogen peroxide (0.86 mL, 7.57mmol, 30% aqueous solution) and the reaction mixture was stirred at roomtemperature for 15 h. The reaction mixture was carefully evaporated todryness. The residue was washed with diethyl ether and dried to obtainthe title compound 5-amino-3-(4-chlorophenyl)isothiazole-4-carbonitrile(0.85 g, crude) as white solid. Calculated (M+H): 236; Found (M+H): 236.

Step-6:

Preparation of 5-amino-3-(4-chlorophenyl)isothiazole-4-carboxamide

A solution of 5-amino-3-(4-chlorophenyl)isothiazole-4-carbonitrile (0.65g, 2.56 mmol) in concentrated sulfuric acid (20 mL) was heated at 100°C. for 15 h. The reaction mixture was cooled and poured into ice-water(25 mL) and extracted with ethyl acetate (3×50 mL). The combined organicextract was washed with brine (25 mL), dried over anhydrous sodiumsulfate and evaporated to obtain the title compound5-amino-3-(4-chlorophenyl)isothiazole-4-carboxamide (0.65 g, crude) asoff white solid. Calculated (M+H): 254.01; Found (M+H): 254.1.

Step-7:

Preparation of 3-(4-chlorophenyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one

To a solution of 5-amino-3-(4-chlorophenyl)isothiazole-4-carboxamide(0.65 g, 2.56 mmol) in acetic anhydride (7 mL) was addedtriethylorthoformate (7 mL) and the reaction mixture was heated at 150°C. for 15 h. The reaction mixture was cooled and poured into ice-water(25 mL). The precipitated solid was filtered, washed with cold water (25mL) and dried to obtain the title compound3-(4-chlorophenyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one (0.65 g, 97%yield) as off white solid. Calculated (M−H): 262; Found (M−H): 262.

Step-8:

Preparation of3-(4-chlorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one

To a stirred solution of3-(4-chlorophenyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one (0.1 g, 0.371mmol) and 2-chloro-1-(pyrrolidin-1-yl)ethanone (0.072 g, 0.493 mmol) inacetone was added potassium carbonate (0.156 g, 1.13 mmol) and thereaction mixture was heated at 50° C. for 15 h. The reaction mixture wasfiltered and the filtrate was evaporated. The crude material waspurified by silica gel column chromatography using 2% methanol indichloromethane to obtain the title compound3-(4-chlorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one(0.03 g, 22% yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.53 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H),4.85 (s, 2H), 3.50 (t, J=6.8 Hz, 2H), 3.29 (t, J=6.4 Hz, 2H), 1.95-1.89(m, 2H), 1.81-1.74 (m, 2H). Calculated (M+H): 375.06; Found (M+H):375.1, HPLC Purity: 99.89%.

Example 381: Preparation of3-(4-chlorophenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one

Step-1:

Preparation of ethyl2-(3-(4-chlorophenyl)-4-oxoisothiazolo[5,4-d]pyrimidin-5(4H)-yl)acetate

To a stirred solution of3-(4-chlorophenyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one (0.54 g, 2.05mmol) and ethyl bromoacetate (0.453 mL, 4.09 mmol) in acetone (20 mL)was added potassium carbonate (0.848 g, 6.14 mmol) and the reactionmixture was heated at 50° C. for 15 h. The reaction mixture was filteredand the filtrate was evaporated. The crude material was purified bysilica gel column chromatography using 3% methanol in dichloromethane toobtain the title compound ethyl2-(3-(4-chlorophenyl)-4-oxoisothiazolo[5,4-d]pyrimidin-5(4H)-yl)acetate(0.25 g, 35% yield) as off white solid. Calculated (M+H): 350.03; Found(M+H): 350.

Step-2:

Preparation of2-(3-(4-chlorophenyl)-4-oxoisothiazolo[5,4-d]pyrimidin-5(4H)-yl)aceticacid

To a stirred solution of ethyl2-(3-(4-chlorophenyl)-4-oxoisothiazolo[5,4-d]pyrimidin-5(4H)-yl)acetate(0.23 g, 65 mmol) in acetic acid (10 mL) was added hydrochloric acid (10mL) and the reaction mixture was heated at 100° C. for 15 h. Then thereaction mixture was cooled and quenched with ice-water. Theprecipitated solid was filtered, washed with water (50 mL) and dried toobtain the title compound2-(3-(4-chlorophenyl)-4-oxoisothiazolo[5,4-d]pyrimidin-5(4H)-yl)aceticacid (0.15 g, crude) as off white solid. Calculated (M+H): 322; Found(M+H): 322.2.

Step-3:

Preparation of3-(4-chlorophenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one

To a stirred solution of2-(3-(4-chlorophenyl)-4-oxoisothiazolo[5,4-d]pyrimidin-5(4H)-yl)aceticacid (0.075 g, 0.23 mmol) in dichloromethane (10 mL) was addedtriethylamine (0.228 mL, 1.63 mmol) and 3,3-difluoroazitidinehydrochloride (0.036 g, 0.28 mmol) at room temperature and the reactionmixture was cooled to 0° C. Then 1-propanephosphonic anhydride (T₃P)(0.22 mL, 0.35 mmol, 50% solution in ethyl acetate) was added dropwiseand the reaction mixture was stirred at room temperature for 15 h. Thereaction mixture was quenched with water (25 mL) and extracted withdichloromethane (3×25 mL). The combined organic extract was washed withbrine (25 mL), dried over anhydrous sodium sulfate, filtered andevaporated. The crude material was purified by silica gel columnchromatography 2% methanol in dichloromethane to obtain the titlecompound 3-(4-chlorophenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)isothiazolo[5,4-d]pyrimidin-4(5H)-one (0.08 g,80% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.53 (s,1H), 7.86 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 4.79-4.73 (m, 4H),4.35 (t, J=8.0 Hz, 2H). Calculated (M+H): 397.03; Found (M+H): 397.2.HPLC Purity: 99.81%.

TABLE 40 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 382

3-(4-chlorophenyl)-5-(2-oxo- 2-(2- (trifluoromethyl)pyrrolidin-1-yl)ethypisothiazolo[5,4- d]pyrimidin-4(5H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.54 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.52 (d, J =8.4 Hz, 2H), 4.98 (s, 2H), 4.69-4.73 (m, 1H), 3.68 (bs, 2H), 1.99-2.05(m, 4H). Calculated (M + H): 443.05; Found (M + H): 443.3. HPLC Purity:99.55%

M. Preparation of Oxazolopyrimidinones Example 383: Preparation of3-(4-chlorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one

Step 1:

Preparation of (E)-4-chlorobenzaldehyde oxime

To a solution of 4-chlorobenzaldehyde (20.0 g, 142.27 mmol) in ethanol(200 mL) were added pyridine (17.2 mL, 213.46 mmol) and hydroxylaminehydrochloride (12.85 g, 184.96 mmol) at room temperature. The resultingmixture was heated to 80° C. and stirred for 4 h. The progress of thereaction was monitored by TLC. The mixture was allowed to cool to roomtemperature and the solvent was removed under reduced pressure. Theresidue was diluted with cold water and stirred for 30 min. Theprecipitated solid was filtered, washed with water and dried undervacuum to obtain title compound (E)-4-chlorobenzaldehyde oxime (21.3 g,95% yield) as off white solid. Calculated (M+H): 156.01; Found (M+1):156.1.

Step 2:

Preparation of (Z)-4-chloro-N-hydroxybenzimidoyl chloride

To a solution of (E)-4-chlorobenzaldehyde oxime (21.3 g, 137.08 mmol) inN, N-dimethylformamide (100 mL) was added N-chlorosuccinimide (23.70 g,178.20 mmol) at room temperature and the reaction mixture was stirred atroom temperature for 3 h. After completion of reaction, the solvent wasremoved under reduced pressure. The residue was diluted with cold waterand stirred for 30 min. The precipitated solid filtered, washed withwater and dried under vacuum to obtain title compound(Z)-4-chloro-N-hydroxybenzimidoyl chloride (17.8 g, 68% yield) as offwhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.94 (s, 1H), 7.79 (d,J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H).

Step 3:

Preparation of 5-amino-3-(4-chlorophenyl)isoxazole-4-carbonitrile

To a suspension of (Z)-4-chloro-N-hydroxybenzimidoyl chloride (2.5 g,13.14 mmol) in methanol was added malononitrile (0.86 g, 13.14 mmol) atroom temperature and stirred for 30 min. The reaction mixture was cooledto 0° C. and sodium methoxide was added portion wise. The resultingmixture was slowly allowed to warm to room temperature and stirred for 3h. Methanol was removed under vacuum, the residue was diluted with coldwater and stirred for 30 min. The precipitated solid was filtered,washed with water and dried under vacuum to afford the title compound5-amino-3-(4-chlorophenyl)isoxazole-4-carbonitrile (2.3 g, 79% yield) aspale brown solid. Calculated (M+H): 220.02; Found (M+1): 220.3.

Step 4:

Preparation of 3-(4-chlorophenyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one

A mixture of 5-amino-3-(4-chlorophenyl)isoxazole-4-carbonitrile (1.25 g,5.69 mmol) and formamide (10 mL) was taken in microwave vial andsubjected to microwave irradiation at 140° C. for 1 h. The reactionmixture was allowed to cool to room temperature and diluted with water(15 mL). The precipitated solid was filtered, washed with water anddried under vacuum to afford the title compound3-(4-chlorophenyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one (1.0 g, crude) asa pale brown solid which was as such taken for next step without furtherpurification. Calculated (M+H): 248.01; Found (M+H): 248.1.

Step 5:

Preparation of3-(4-chlorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one

To a mixture of 3-(4-chlorophenyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one(0.2 g, 0.80 mmol) and potassium carbonate (0.33 g, 2.42 mmol) in dryacetone was added 2-chloro-1-(pyrrolidin-1-yl)ethanone (0.23 g, 1.61mmol). The resulting mixture was heated at 55° C. for 3 h. Aftercompletion of the reaction (monitored by TLC), the mixture was allowedto cool to room temperature and filtered. The solid was washed withethyl acetate and the combined filtrate was concentrated under vacuum toafford crude product which was purified by silica gel (60-120) columnchromatography using 3% methanol in dichloromethane to afford the titlecompound3-(4-chlorophenyl)-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one(0.15 g, 53% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.65 (s, 1H), 8.27 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 4.89 (s,2H), 3.53 (t, J=6.4 Hz, 2H), 3.31 (t, J=6.4 Hz, 2H), 1.94-1.90 (m, 2H),1.82-1.76 (m, 2H). Calculated (M+H): 359.08; Found (M+1): 359.1; HPLCpurity: 99.72%.

TABLE 41 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical data 384

3-(4-chlorophenyl)-5- (2-oxo-2-(2- (trifluoromethyl) pyrrolidin-1-yl)ethyl)isoxazolo[5,4- d]pyrimidin-4(5H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.67 (s, 1H), 8.26 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4Hz, 2H), 5.17-4.91 (m, 2H), 4.73 (brs, 1H), 3.7 (brs, 2H), 2.18-1.93 (m,4H). Calculated (M + H): 427.07, Found (M + H): 427.1. HPLC purity:99.62%.

Example 385: Preparation of3-(4-chlorophenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one

Step 1:

Preparation of ethyl2-(3-(4-chlorophenyl)-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl)acetate

To a mixture of 3-(4-chlorophenyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one(0.8 g, 3.23 mmol) and potassium carbonate (1.34 g, 9.71 mmol) in dryacetone (80 mL) was added ethyl 2-bromoacetate (0.72 g, 6.46 mmol). Theresulting mixture was heated to 55° C. and stirred for 3 h. The reactionmixture was allowed to cool to room temperature and filtered. The solidwas washed with ethyl acetate and the combined filtrate was concentratedunder vacuum to afford crude product which was purified by silica gel(60-120) column chromatography using 35% ethyl acetate in hexane toafford the title compound ethyl2-(3-(4-chlorophenyl)-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl)acetate(0.62 g, 62% yield) as white solid. Calculated (M+H): 334.05; Found(M+1): 334.1.

Step 2:

Preparation of2-(3-(4-chlorophenyl)-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl)aceticacid

A suspension of ethyl2-(3-(4-chlorophenyl)-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl)acetate(0.25 g, 0.75 mmol) in a mixture of 1.5 N hydrochloric acid (5 mL) andacetic acid (5 mL) was heated to 120° C. and stirred for 4 h. Thereaction mixture was gradually allowed to warm to room temperature anddiluted with cold water. The precipitated solid was filtered, washedwith water and dried under vacuum to obtain the title compound2-(3-(4-chlorophenyl)-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl)aceticacid (0.2 g, 87% yield) as a white solid. Calculated (M+H): 306.02;Found (M+H): 306.0.

Step 3:

Preparation of3-(4-chlorophenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one

To a solution of2-(3-(4-chlorophenyl)-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl)aceticacid (0.1 g, 0.32 mmol) in dichloromethane (15 mL), were added3,3-difluoroazetidine hydrochloride (0.04 g, 0.32 mmol) andtriethylamine (0.22 mL, 1.63 mmol). The reaction mixture was cooled toroom temperature and 1-propanephosphonic anhydride (T₃P) (0.41 mL, 0.65mmol, 50% solution in ethyl acetate) was added and mixture was allowedto warm to room temperature and stirred for 16 h. The reaction mixturewas diluted with dichloromethane (25 mL), washed with water (2×50 mL),brine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford crude product which was purified bysilica gel column chromatography using 3% methanol in dichloromethane aseluent to afford the title compound3-(4-chlorophenyl)-5-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one(0.057 g, 47.5% yield) as white solid. ¹H NMR (400 MHz, DMSO-d6) δ(ppm): 8.67 (s, 1H), 8.25 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H),4.82-4.75 (m, 4H), 4.37 (t, J=12 Hz, 2H). Calculated (M+H): 381.05;Found (M+1): 381.3. HPLC purity: 99.87%.

TABLE 42 The following compound was prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical data 386

3-(4-chlorophenyl)-5- (2-(3-fluoropyrrolidin- 1-yl)-2-oxoethyl)isoxazolo [5,4-d]pyrimidin-4(5H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.67 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 8.4 Hz, 2H), 7.63(d, J = 8.4 Hz, 2H), 5.39 (t, J = 49.6 Hz,1H), 5.01- 4.83 (m, 2H),3.93-3.40 (m, 4H), 2.25-1.96 (m, 2H); Calculated (M + H): 377.07, Found(M + H): 377.4; HPLC purity: 99.76%

Example 387: Preparation of5-(4-chlorophenyl)-3-(2-oxo-2-(3-(trifluoromethyl)cyclopentypethyl)furo[2,3-d]pyrimidin-4(3H)-one

Step-1:

Preparation of 2-bromo-1-(4-chlorophenyl)ethanone

To a stirred solution of 1-(4-chlorophenyl)ethanone (6.0 g, 38.96 mmol)in acetic acid (15 mL) at room temperature was added pyridiniumtribromide (13.67 g, 42.85 mmol) and stirred at RT for 18 h. Reactionmixture was diluted with ice water (100 mL) and the precipitate wasfiltered through the sintered glass funnel, washed with water (50 mL)and dried by using high vacuum to afford compound2-bromo-1-(4-chlorophenyl)ethanone (9.0 g, 99.0% yield) as off whitesolid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.93 (d, J=8.4 Hz, 2H), 7.47 (d,J=8.4 Hz, 2H), 4.40 (s, 2H).

Step-2:

Preparation of 1-(4-chlorophenyl)-2-hydroxyethanone

To a stirred solution of 2-bromo-1-(4-chlorophenyl)ethanone (9.0 g,38.96 mmol) in mixture of ethanol and water (7:3) 180 (mL), sodiumformate (16.4 g, 241.15 mmol) was added at room temperature and stirredat 100° C. for 12 h. The solvent was removed under vacuum and theresulting crude product was diluted with water (100 mL) and theprecipitate was filtered through the sintered funnel and was washed withwater (50 mL) and the solid was dried under high vacuum to affordcompound 1-(4-chlorophenyl)-2-hydroxyethanone (5.5 g, 80.0% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm): 7.93 (d, J=8.0 Hz,2H), 7.58 (d, J=8.4 Hz, 2H), 5.11 (t, J=5.2 Hz, 1H), 4.76 (d, J=5.6 Hz,2H).

Step-3:

Preparation of 2-amino-4-(4-chlorophenyl)furan-3-carbonitrile

To a stirred solution of 1-(4-chlorophenyl)-2-hydroxyethanone (5.0 g,29.41 mmol) in methanol (50 mL), diethyl amine (1.25 mL, 11.76 mmol) wasadded at room temperature and followed by malononitrile (2.1 g, 32.45mmol). Reaction mixture was stirred at room temperature for 3 h. Thesolvent was removed under vacuum and the resulting crude material wasdiluted with water (100 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layer was dried over anhydrous sodium sulfate andconcentrated to get crude compound which was purified by columnchromatography using 50% ethyl acetate in hexane to afford titlecompound 2-amino-4-(4-chlorophenyl)furan-3-carbonitrile (4.1 g, 66.0%yield) as off white solid. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 7.48 (d,J=8.4 Hz, 2H), 7.39 (d, J 8.8 Hz, 2H), 6.99 (s, 1H), 4.85 (s, 2H).Calculated M+H: 219.02; Found M+H: 219.1.

Step-4:

Preparation of N-(4-(4-chlorophenyl)-3-cyanofuran-2-yl)formamide

To a stirred solution of 2-amino-4-(4-chlorophenyl)furan-3-carbonitrile(10.0 g, 45.87 mmol) in formic acid (120 mL) at 0° was added aceticanhydride (120 mL). The reaction mixture was stirred at room temperaturefor 1 h. The reaction mixture was diluted with ice cold water (50 mL)and the precipitate was filtered through the sintered funnel and washedwith water (150 mL) and the solid was dried under high vacuum to affordthe title compound N-(4-(4-chlorophenyl)-3-cyanofuran-2-yl)formamide(5.0 g, 42.0% yield) as pale pink solid. ¹H NMR (400 MHz, DMSO-d₆), δ(ppm): 11.63 (s, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 7.63 (d, J=8.4 Hz,2H), 7.56 (d, J=8.8 Hz, 2H). Calculated M+H: 247.02; Found M+H: 247.1.

Step-5:

Preparation of 5-(4-chlorophenyl)furo[2,3-d]pyrimidin-4(3H)-one

The solution of N-(4-(4-chlorophenyl)-3-cyanofuran-2-yl)formamide (1.5g, 60.72 mmol) in acetic acid (3.0 mL) was taken in microwave vial andit was heated at 170° C. in CEM microwave for 1 h. The reaction mixturewas diluted with ice cold water (50 mL) and the precipitate was filteredthrough the sintered funnel, washed with water (150 mL) and dried underhigh vacuum to afford compound5-(4-chlorophenyl)furo[2,3-d]pyrimidin-4(3H)-one (1.4 g, 66.0% yield) asoff white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.71 (s, 1H), 8.29(s, 1H), 8.15 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.47 (d, J=8 Hz, 2H).Calculated M+H: 247.02; Found M+H: 247.0.

Step-6:

Preparation of ethyl ethyl2-(5-(4-chlorophenyl)-4-oxofuro[2,3-d]pyrimidin-3(4H)-yl)acetate

To a stirred solution of5-(4-chlorophenyl)furo[2,3-d]pyrimidin-4(3H)-one (1.0 g, 4.04 mmol) inacetone (20 mL) at room temperature was added potassium carbonate (1.6g, 12.14 mmol) followed by ethyl bromoacetate (1.47 mL, 8.09 mmol). Thereaction mixture was heated to 55° C. for 4 h. The reaction mixture wasfiltered through the sintered funnel and washed with 10% methanol indichloromethane (50 mL). The filtrate was concentrated to yield thecrude compound which was purified by column chromatography using 30%ethyl acetate in hexane to get the title compound—ethyl2-(5-(4-chlorophenyl)-4-oxofuro[2,3-d]pyrimidin-3(4H)-yl)acetate (1.2 g,92.0% yield) as off white solid. Calculated M+H: 333.06; Found M+H:333.1.

Step-7:

Preparation of2-(5-(4-chlorophenyl)-4-oxofuro[2,3-d]pyrimidin-3(4H)-yl)acetic acid

To a stirred solution of ethyl2-(5-(4-chlorophenyl)-4-oxofuro[2,3-d]pyrimidin-3(4H)-yl)acetate (1.2 g,3.60 mmol) in tetrahydrofuran and water (1:1) (20 mL) at roomtemperature was added lithium hydroxide monohydrate (18.01, 1.08 g).Reaction mixture was stirred at room temperature for 1 h. The reactionmixture was evaporated and the resulting crude material was acidifiedwith 1.5 N HCl (pH 2-3). The precipitate was filtered through thesintered funnel and washed with water (20 mL) and dried under vacuum togive the title compound2-(5-(4-chlorophenyl)-4-oxofuro[2,3-d]pyrimidin-3(4H)-yl)acetic acid(0.8 g, 73.0% yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆), δ(ppm): 13.25 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.98 (d, J=8.4 Hz,2H), 7.48 (d, J=8.8 Hz, 2H), 4.76 (s, 2H).

Step-8:

Preparation of5-(4-chlorophenyl)-3-(2-oxo-2-(3-(trifluoromethyl)pyrrolidin-1-yl)ethyl)furo[2,3-d]pyrimidin-4(3H)-one

To a stirred solution of2-(5-(4-chlorophenyl)-4-oxofuro[2,3-d]pyrimidin-3(4H)-yl)acetic acid(0.15 g, 0.49 mmol) in dichloromethane (20 mL) at room temperature wasadded triethylamine (0.21 mL, 2.96 mmol) stirred for 10 min and3-(trifluoromethyl)pyrrolidine (0.082 g, 0.59 mmol) was added. Finallypropyl phosphonic anhydride (50% solution) (0.21 mL, 0.74 mmol) wasadded and stirred at room temperature for 16 h. Reaction mixture wasdiluted with water (50 mL) and extracted with dichloromethane (3×50 mL).Combined organic layers were dried over anhydrous sodium sulfate andconcentrated to get the crude compound. The crude material was purifiedby silica gel column chromatography using 5% methanol in dichloromethaneto afford the title compound5-(4-chlorophenyl)-3-(2-oxo-2-(3-(trifluoromethyl)cyclopentypethyl)furo[2,3-d]pyrimidin-4(3H)-one(0.033 g, 7.0% yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.40 (s, 1H), 8.34 (s, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.48 (d,J=8.4 Hz, 2H), 5.14-4.72 (m, 4H), 3.71 (s, 2H), 2.31-1.93 (m, 4H).Calculated (M+H): 426.08; Found (M+H): 426.3; HPLC purity: 99.72%.

TABLE 43 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 388

5-(4-chlorophenyl)-3- (2-oxo-2-(pyrrolidin-1- yl)ethyl)furo[2,3-d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ (ppm): 8.38 (s, 1H),8.33 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.86(s, 2 H), 3.54 (t, J = 6.4 Hz, 2H), 3.31(t, J = 6.8 Hz, 2H), 1.97-1.922(m, 2H), 1.83- 1.78 (m, 2H). Calculated M + H: 358.09; Found M + H:358.0 HPLC purity: 99.21%. 389

5-(4-chlorophenyl)-3- (2-(3,3-difluoroazetidin- 1-yl)-2-oxoethyl)furo[2,3- d]pyrimidin-4(3H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 8.40 (s, 1H), 8.33 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.48 (s, J= 8.4 Hz, 2H), 4.78 (s, 4 H), 4.38 (t, J = 12.0 Hz, 2H). Calculated M +H: 380.05; Found M + H: 380.01 HPLC purity: 99.42%.

N. Preparation of Pyrrolopyrazinones Example 390: Preparation of8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolo[1,2-a]pyrazin-1(2H)-one

Step-1:

Preparation of methyl pyrrolidine-2-carboxylate

To a solution of L-proline (6 g, 52.11 mmol) in methanol (50 mL) cooledto 0° C., was added thionyl chloride (4.92 mL, 67.74 mmol) drop-wise andthe reaction mixture was stirred at room temperature for 18 h. Thereaction mixture was concentrated to afford the title compound methylpyrrolidine-2-carboxylate (9.6 g, crude) as a colourless liquid.Calculated (M+H): 130.08; Found (M+H): 130.2.

Step-2:

Preparation of 1-tert-butyl 2-methyl pyrrolidine-1,2-dicarboxylate

To a solution of methyl pyrrolidine-2-carboxylate (9.6 g, 74.41 mmol)and triethylamine (15.55 mL, 111.62 mmol) in dichloromethane (200 mL)cooled to 0° C., was added Boc anhydride (20.5 mL, 89.30 mmol) drop-wiseand the reaction mixture was stirred at room temperature for 18 h. Thereaction mixture was diluted with dichloromethane (200 mL) and washedwith water (2×200 mL). The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated. The crude product was purified bysilica gel column chromatography using 20% ethyl acetate in hexane toafford the title compound 1-tert-butyl 2-methylpyrrolidine-1,2-dicarboxylate (11 g, 93% yield) as a colourless liquid.Calculated (M+H): 230.13; Found (M+H): 130.2 [Boc deprotected massobserved].

Step-3:

Preparation of 1-tert-butyl 2-methyl3-bromo-1H-pyrrole-1,2-dicarboxylate

To a solution of 1-tert-butyl 2-methyl pyrrolidine-1,2-dicarboxylate(2.5 g, 10.90 mmol) in carbon tetrachloride (1.25 L), was addedN-bromosuccinimide (6.87 g, 38.60 mmol) and the reaction mixture washeated at 85° C. for 2 h (observed succinimide precipitation and brominevapours after completion of reaction). The reaction mixture was cooledto 0° C. and stirred for 15 minutes. The precipitated solid was filteredoff and the filtrate was concentrated. The crude product was purified bysilica gel column chromatography using 10% ethyl acetate in hexane toafford the title compound 1-tert-butyl 2-methyl3-bromo-1H-pyrrole-1,2-dicarboxylate (1.7 g, 51% yield) as a brownishliquid. ¹H NMR (400 MHz, CDCl3) δ (ppm): 7.21 (d, J=3.2 Hz, 1H), 6.22(d, J=3.6 Hz, 1H), 3.89 (s, 3H), 1.54 (s, 9H).

Step-4:

Preparation of 1-tert-butyl 2-methyl3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-1,2-dicarboxylate

To a solution of 1-tert-butyl 2-methyl3-bromo-1H-pyrrole-1,2-dicarboxylate (2.5 g, 8.21 mmol),(4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (3.59 g, 17.26 mmol)and potassium carbonate (9.08 g, 65.75 mmol) in toluene:water mixture(70 mL, 1:1), tetrabutyl ammonium bromide (0.23 g, 0.73 mmol) was addedand the reaction mixture was purged with argon for 15 minutes. Thentetrakis(triphenylphosphine)palladium (0) (0.189 g, 0.16 mmol) was addedand the reaction mixture was heated at 110° C. for 18 h. The reactionmixture was diluted with ethyl acetate (100 mL) and washed with water(2×50 mL). The organic layer was dried over anhydrous sodium sulphate,filtered and concentrated. The crude product was purified by silica gelcolumn chromatography using 15% ethyl acetate in hexane to afford thetitle compound 1-tert-butyl 2-methyl3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-1,2-dicarboxylate (1.7g, 53% yield) as a brownish gum. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.80-7.78 (m, 2H), 7.54 (t, J=10 Hz, 1H), 7.44 (d, J=3.2 Hz, 1H), 6.62(d, J=3.6 Hz, 1H), 3.74 (s, 3H), 1.51 (s, 9H).

Step-5:

Preparation of methyl3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate

To a solution of 1-tert-butyl 2-methyl3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-1,2-dicarboxylate (1.7g) in dichloromethane (20 mL) cooled to 0° C., was added trifluoroaceticacid (2 ml) and the reaction mixture was stirred at room temperature for3 h. After completion of the reaction (as monitored by TLC), thereaction mixture was concentrated, the residue was basified withsaturated sodium bicarbonate solution (30 mL) and extracted withdichloromethane (2×50 mL). The combined organic layer was dried overanhydrous sodium sulphate, filtered and concentrated. The crude productwas purified by silica gel column chromatography using 60% ethyl acetatein hexane to afford the title compound methyl3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate (1.15 g,91% yield) as a brownish gum. Calculated (M−H): 286.06; Found (M−H):286.

Step-6:

Preparation of methyl1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate

To a suspension of sodium hydride (0.022 g, 0.54 mmol, 60% dispersion inmineral oil) in N-methyl pyrrolidine (5 mL) cooled to 0° C., was added asolution of methyl3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate (0.15 g,0.52 mmol) in N-methyl pyrrolidine (5 mL) drop-wise and the reactionmixture was stirred at room temperature for 1 h. Then2-bromo-1,1-dimethoxyethane (0.097 g, 0.57 mmol) was added and thereaction mixture was heated at 130° C. for 4 h. The reaction mixture wasdiluted with ice water (30 mL) and extracted with ethyl acetate (2×60mL). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated. The crude product was purified bysilica gel column chromatography using 40% ethyl acetate in hexane toafford the title compound methyl1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate(0.13 g, 66% yield) as a colourless liquid. ¹H NMR (400 MHz, CDCl3) δ(ppm):

7.60 (d, J=6 Hz, 1H), 7.52 (bs, 1H), 7.15 (t, J=9.2 Hz, 1H), 6.91 (d,J=2 Hz, 1H), 6.15 (d, J=2 Hz, 1H), 4.58 (t, J=5.6 Hz, 1H), 4.39 (d,J=5.6 Hz, 2H), 3.64 (s, 3H), 3.40 (s, 6H).

Step-7:

Preparation of1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylicacid

To a solution of methyl1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate(0.17 g, 0.45 mmol) in ethanol:water mixture (10 mL, 1:1), lithiumhydroxide monohydrate was added and the reaction mixture was heated at75° C. for 8 h. The reaction mixture was concentrated to remove ethanol.The residue was diluted with water (15 mL), neutralized with acetic acidand extracted with ethyl acetate (2×50 mL). The combined organic layerwas dried over anhydrous sodium sulphate, filtered and concentrated toafford the title compound1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylicacid (0.15 g, 92% yield) as a brownish solid. Calculated (M−H): 360.09;Found (M−H): 360.1.

Step-8:

Preparation of1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamide

To a solution of1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylicacid (0.15 g, 0.41 mmol) in a mixture of N-methyl pyrrolidine (1.5 mL)and ammonia in dioxane (4 mL, 0.5M), HATU (0.31 g, 0.83 mmol) was addedand the reaction mixture was stirred at room temperature for 18 h.Additional 1 equivalent of HATU and N-methyl pyrrolidine (5 mL) wereadded and the reaction mixture was purged with ammonia gas until thecompletion of the reaction (20 minutes). The reaction mixture wasdiluted with brine solution (20 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated. The crude product was purified bysilica gel column chromatography using 3% methanol in dichloromethane toafford the title compound1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamide(0.12 g, 80% yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.68-7.65 (m, 2H), 7.45 (t, J=10 Hz, 1H), 7.38 (bs, 1H), 7.30(bs, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 4.52 (t, J=5.2Hz, 1H), 4.15 (d, J=5.2 Hz, 2H), 3.23 (s, 6H).

Step-9:

Preparation of8-(4-fluoro-3-(trifluoromethyl)phenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one

A mixture of1-(2,2-dimethoxyethyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamide(0.12 g) and acetic acid (6 mL) was heated at 105° C. for 4 h. Thereaction mixture was concentrated, the residue was diluted with water(20 mL), basified with aqueous ammonia and extracted with ethyl acetate(2×50 mL). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated to afford the title compound8-(4-fluoro-3-(trifluoromethyl)phenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one(0.1 g, crude) as a brownish solid. Calculated (M+H): 297.06; Found(M+H): 297.1.

Step-10:

Preparation of ethyl2-(8-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxopyrrolo[1,2-a]pyrazin-2(1H)-yl)acetate

A mixture of8-(4-fluoro-3-(trifluoromethyl)phenyl)pyrrolo[1,2-a]pyrazin-1(2H)-one(0.097 g, 0.32 mmol), ethyl 2-bromoacetate (0.07 mL, 0.65 mmol) andpotassium carbonate (0.135 g, 0.98 mmol) in acetone (10 mL) was heatedat 65° C. for 3 h. The reaction mixture was filtered and the filtratewas concentrated. The crude product was purified by silica gel columnchromatography using 15% ethyl acetate in hexane to afford the titlecompound ethyl2-(8-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxopyrrolo[1,2-a]pyrazin-2(1H)-yl)acetate(0.09 g, 72% yield) as a brownish gum. Calculated (M+H): 383.09; Found(M+H): 383.1.

Step-11:

Preparation of2-(8-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxopyrrolo[1,2-a]pyrazin-2(1H)-yl)aceticacid

To a stirred solution of ethyl2-(8-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxopyrrolo[1,2-a]pyrazin-2(1H)-yl)acetate(0.09 g, 0.23 mmol) in tetrahydrofuran:water mixture (10 mL, 1:1) cooledto 0° C., was added lithium hydroxide monohydrate (0.049 g, 1.17 mmol)and the reaction mixture was stirred at the same temperature for 20minutes. The reaction mixture was diluted with water (15 mL), acidifiedwith 1.5N hydrochloric acid and extracted with ethyl acetate (2×35 mL).The combined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated to afford the title compound2-(8-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxopyrrolo[1,2-a]pyrazin-2(1H)-yl)aceticacid (0.08 g, crude) as a brownish solid. Calculated (M+H): 355.06;Found (M+H): 355.1.

Step-12:

Preparation of8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolo[1,2-a]pyrazin-1(2H)-one

To a stirred solution of2-(8-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxopyrrolo[1,2-a]pyrazin-2(1H)-yl)aceticacid (0.08 g, 0.22 mmol) in dichloromethane (20 mL) was addedtriethylamine (0.25 mL, 1.80 mmol) at room temperature and stirred for10 minutes. 3-fluoropyrrolidine hydrochloride (0.043 g, 0.33 mmol) wasadded and the reaction mixture was cooled to 0° C. Then1-propanephosphonic anhydride solution (T_(S)P) (0.21 mL, 0.33 mmol, 50%in ethyl acetate) was added and the reaction mixture was stirred at roomtemperature for 1 h. The solution was diluted with dichloromethane (50mL) and washed with water (2×30 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to get the crudecompound which was purified by silica gel column chromatography using 3%methanol in dichloromethane to afford the title compound8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolo[1,2-a]pyrazin-1(2H)-one(0.055 g, 57% yield) as white solid. Calculated (M+H): 426.12; Found(M+H): 426.1. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.10 (d, J=5.6 Hz, 1H),7.97 (t, J=5.6 Hz, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.45 (t, J=10.8 Hz, 1H),7.39 (d, J=6 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.78-6.76 (m, 1H),5.48-5.24 (m, 1H), 4.75-4.57 (m, 2H), 3.86-3.20 (m, 4H), 2.30-1.92 (m,2H). HPLC purity: 99.99%.

TABLE 44 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical Data 391

8-(4-fluoro-3- (trifluoromethyl) phenyl)-2-(2-oxo-2- (pyrrolidin-1-yl)ethyl)pyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.10 (d, J = 6.8 Hz, 1H), 7.97 (bs, 1H), 7.51 (s, 1H), 7.45 (t, J= 9.6 Hz, 1H), 7.38 (d, J = 6 Hz, 1H), 6.84 (s, 1H), 6.75 (d, J = 6 Hz,1H), 4.60 (s, 2H), 3.47 (t, J = 6.8 Hz, 2H), 1.92-1.84 (m, 2H),1.80-1.72 (m, 2H). 2H were merged with DMSO water peak. Calculated (M +H): 408.13; Found (M + H): 408.1. HPLC purity: 99.48% 392

8-(3-chloro-4- fluorophenyl)-2- (2-oxo-2- (pyrrolidin-1-yl)ethyl)pyrrolo[1,2- a]pyrazin-1(2H)- one ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 7.93 (dd, J₁ = 1.6 Hz, 7.6 Hz, 1H), 7.62-7.68 (m, 1H), 7.49 (d, J= 2.8 Hz, 1H), 7.37-7.33 (m, 2H), 6.79 (d, J = 2.8 Hz, 1H), 6.74 (d, J =6.0 Hz, 1H), 4.59 (s, 2H), 3.47 (t, J = 6.8 Hz, 2H), 3.32-3.22 (m, 2H),1.79-1.73 (m, 2H). 2H merged with DMSO water peak. Calculated (M + H):374.10, found (M + H): 374.1, HPLC purity: 99.64% 393

8-(3-chloro-4- fluorophenyl)-2- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one 1H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 7.93 (d, J = 5.6 Hz, 1H), 7.62-7.69 (m, 1H), 7.50 (d, J = 2.8 Hz,1H), 7.38-7.33 (m, 2H), 6.79 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 5.6 Hz,1H), 5.40-5.50 (m, 1H), 4.74-4.58 (m, 2H), 3.75-3.27 (m, 4H), 2.30-2.07(m, 2H). Calculated (M + H): 392.09, found (M + H): 392.1, HPLC purity:95.15% 394

8-(3,4- dichlorophenyl)-2- (2-oxo-2- (pyrrolidin-1-yl)ethyl)pyrrolo[1,2- a]pyrazin-1(2H)- one 1H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.02 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.56(d, J = 8.8 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.38 (d, J = 5.6 Hz, 1H),6.83 (d, J = 2.8 Hz, 1H), 6.76 (d, J = 6.0 Hz, 1H), 4.61 (s, 2H), 3.47(t, J = 6.4 Hz, 2H), 3.32-3.22 (m, 2H), 1.95-1.88 (m, 2H), 1.80-1.73 (m,2H). Calculated (M + H): 390.07; Found (M + H): 390.0. HPLC Purity:99.77% 395

8-(3,4- dichlorophenyl)-2- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.02 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 1.2 Hz, 8.4 Hz, 1H), 7.56(d, J = 8.4 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.39 (d, J = 5.6 Hz, 1H),6.84 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 2.0 Hz, 5.6 Hz, 1H), 5.49-5.24(m, 1H), 4.76-4.58 (m, 2H), 3.87-3.22 (m, 4H), 2.30-1.93 (m, 2H).Calculated (M + H): 408.06; Found (M + H): 408.1. HPLC Purity: 99.52%396

8-(3,4- dichlorophenyl)-2- (2-(3-fluoro-3- methylazetidin-1- yl)-2-oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.02 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H),7.52 (d, J = 2 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 6.84 (d, J = 1.6 Hz,1H), 6.77 (d, J = 6 Hz, 1H), 4.49 (s, 2H), 4.39-4.26 (m, 2H), 3.96 (d, J= 20.4 Hz, 2H), 1.58 (d, J = 22 Hz, 3H). Calculated (M + H): 408.06;Found (M + H): 408.0. HPLC purity: 99.07%. 397

8-(3-chloro-4- fluorophenyl)-2- (2-(3-fluoro-3- methylazetidin-1- yl)-2-oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ(ppm): 7.94 (dd, J = 2.0, 7.2 Hz, 1H), 7.66-7.62 (m, 1H), 7.50 (d, J =2.8 Hz, 1H), 7.39-7.33 (m, 2H), 6.80 (d, J = 2.8 Hz, 1H), 6.75 (d, J = 6Hz, 1H), 4.48 (s, 2H), 4.38- 4.25 (m, 2H), 4.02-3.94 (m, 2H), 1.58 (d, J= 22 Hz, 3H). Calculated (M + H): 392.09, found (M + H): 392.2, HPLCpurity: 99.89%. 398

8-(3-chloro-4- fluorophenyl)-2- (2-(3-cyclopropyl- 3-fluoroazetidin-1-yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 7.96-7.94 (m, 1H), 7.66- 7.64 (m, 1H), 7.50 (d, J =2.8 Hz, 1H), 7.39-7.34 (m, 2H), 6.80-6.76 (m, 2H), 4.53-4.43 (m, 2H),4.29- 4.17 (m, 2H), 3.93-3.82 (m, 2H), 1.40-1.34 (m, 1H), 0.62-0.42 (m,4H). Calculated (M + H): 418.11; Found (M + H): 418.1. HPLC Purity:99.09% 399

8-(3-chloro-4- fluorophenyl)-2- (2-(3-fluoro-3- phenylazetidin-1- yl)-2-oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.96-7.94 (m, 1H), 7.67- 7.65 (m, 1H), 7.55-7.51 (m, 3H),7.48-7.34 (m, 5H), 6.81-6.79 (m, 2H), 4.81-4.68 (m, 2H), 4.58 (s, 2H),4.35 (d, J = 20.0 Hz, 2H). Calculated (M + H): 454.11; Found (M + H):454.1. HPLC Purity: 97.38% 400

8-(3-chloro-4- fluorophenyl)-2- (2-(3-ethyl-3- fluoroazetidin-1- yl)-2-oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one 1H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.94 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 7.66-7.62 (m, 1H), 7.51 (d, J= 2.8 Hz, 1H), 7.39-7.34 (m, 2H), 6.80 (d, J = 2.4 Hz, 1H), 6.76 (d, J =5.6 Hz, 1H), 4.54- 4.45 (m, 2H), 4.37-4.25 (m, 2H), 4.02-3.88 (m, 2H),1.93-1.82 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). Calculated (M + H): 406.11;Found (M + H): 406.1. HPLC Purity: 99.84% 401

8-(4-fluoro-3- (trifluoromethyl) phenyl)-2-(2-(3- fluoro-3-methylazetidin-1- yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.13 (d, J = 6.4 Hz, 1H), 7.97 (brs,1H), 7.53 (d, J = 2 Hz, 1H), 7.46 (t, J = 10 Hz, 1H), 7.41 (d, J = 6 Hz,1H), 6.85 (d, J = 2 Hz, 1H), 6.78 (d, J = 6 Hz, 1H), 4.52 (s, 2H), 4.48(m, 2H), 3.98 (d, J = 18.8 Hz, 2H), 1.60 (d, J = 22 Hz, 3H). Calculated(M + H): 426.1; Found (M + H): 426.1. HPLC purity: 99.86% 402

8-(3-chloro-4- fluorophenyl)-2- (2-(3-fluoro-3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm); 7.94 (d, J = 5.6 Hz, 1H), 7.64 (brs, 1H), 7.50(d, J = 2.4 Hz, 1H), 7.39-7.33 (m, 2H), 6.80 (d, J = 2.4 Hz, 1H), 6.75(d, J = 5.6 Hz, 1H), 4.88-4.71 (m, 2H), 4.50 (s, 2H), 4.46-4.35 (m, 2H),4.13-3.96 (m, 2H). Calculated (M + H): 410.08; Found (M + 1): 410.1.HPLC purity 98.01%. 403

8-(3,4- dichlorophenyl)-2- (2-(3-fluoro-3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm); 8.02 (d, J = 2 Hz, 1H), 7.71-7.41 (m, 3H), 7.38(d, J = 10.4 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 6.77 (d, J = 6.0 Hz,1H), 4.89-4.71 (m, 2H), 4.51-4.35 (m, 4H), 4.13-3.96 (m, 2H). Calculated(M + H): 426.05; Found (M + 1): 426.0. HPLC purity 98.10% 404

8-(5,6- dichloropyridin-3- yl)-2-(2-(3-fluoro- 3-methylazetidin-1-yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.66 (s, 1H), 8.50 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H),7.44 (d, J = 5.6 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 5.6 Hz,1H), 4.51 (s, 2H), 4.37-4.26 (m, 2H), 3.96 (d, J = 20 Hz, 2H), 1.58 (d,J = 22 Hz, 3H). Calculated (M + H): 409.06; Found (M + H): 409.0. HPLCpurity: 99.20%. 405

8-(5,6- dichloropyridin-3- yl)-2-(2-(3-ethyl- 3-fluoroazetidin-1- yl)-2-oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.66 (s, 1H), 8.50 (s, 1H), 7.57 (d, J = 2 Hz, 1H), 7.44 (d, J =5.6 Hz, 1H), 6.97 (s, 1H), 6.82 (d, J = 5.6 Hz, 1H), 4.56 (s, 2H),4.52-4.28 (m, 2H), 4.02-3.88 (m, 2H), 1.91-1.83 (m, 2H), 0.91 (t, J =7.2 Hz, 3H). Calculated (M + H): 423.07; Found (M + H): 423.1. HPLCpurity: 99.53%. 406

8-(5,6- dichloropyridin-3- yl)-2-(2-(3-fluoro- 3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.66 (d, J = 2 Hz, 1H), 8.50 (d, J = 1.6 Hz, 1H),7.58 (d, J = 2 Hz, 1H), 7.44 (d, J = 5.6 Hz, 1H), 6.97 (d, J = 2 Hz,1H), 6.82 (d, J = 6 Hz, 1H), 4.89-4.71 (m, 2H), 4.53 (s, 2H), 4.50-4.36(m, 2H), 4.13-3.96 (m, 2H). Calculated (M + H): 427.05; Found (M + H):427.2. HPLC purity: 99.91%. 407

2-(2-(3-fluoro-3- (fluoromethyl) azetidin-1-yl)-2- oxoethyl)-8-(4-fluoro-3- (trifluoromethyl) phenyl)pyrrolo[1,2- a]pyrazin-1(2H)- one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.13 (d, J = 6.4 Hz, 1H), 7.97 (brs,1H), 7.53 (d, J = 2.0 Hz, 1H), 7.47 (t, J = 9.6 Hz, 1H), 7.41 (d, J =5.6 Hz, 1H), 6.86 (s, 1H), 6.76 (d, J = 6.0 Hz, 1H), 4.88-4.70 (m, 2H),4.51-4.36 (m, 4H), 4.13-3.96 (m, 2H). Calculated (M + H): 444.11; Found(M + H): 444.1. HPLC Purity: 98.77% 408

8-(6-chloro-5- methylpyridin-3- yl)-2-(2-(3-fluoro- 3-methylazetidin-1-yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm); 8.48 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H),7.54 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 6.83 (d, J = 2.4 Hz,1H), 6.78 (d, J = 5.6 Hz, 1H), 4.48 (s, 2H), 4.39-4.25 (m, 2H),3.99-3.94 (m, 2H), 2.33 (s, 3H), 1.58 (d, J = 22.4 Hz, 3H). Calculated(M + H): 389.11; Found (M + 1): 389.1. HPLC purity 99.03% 409

8-(6-chloro-5- methylpyridin-3- yl)-2-(2-(3-fluoro- 3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm); 8.48 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 1.6 Hz,1H), 7.55 (d, J = 2.8 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 6.84 (d, J =2.8 Hz, 1H), 6.77 (d, J = 5.6 Hz, 1H), 4.88- 4.71 (m, 2H), 4.51 (s, 2H),4.47- 4.38 (m, 2H), 4.13-3.99 (m, 2H), 2.33 (s, 3H). Calculated (M + H):407.10; Found (M + 1): 407.1. HPLC purity 99.22% 410

8-(6-chloro-5- methylpyridin-3- yl)-2-(2-(3-ethyl- 3-fluoroazetidin-1-yl)-2- oxoethyl)pyrrolo [1,2-a]pyrazin- 1(2H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm); 8.48 (d, J = 2.4 Hz, 1H), 8.06 (s, 1H), 7.54 (d, J =2.4 Hz, 1H), 7.41 (d, J = 6.0 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.78(d, J = 5.6 Hz, 1H), 4.49 (s, 2H), 4.34-4.25 (m, 2H), 4.01-3.87 (m, 2H),2.34 (s, 3H), 1.93-1.81 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H). Calculated(M + H): 403.13; Found (M + 1): 403.1. HPLC purity 99.21%

Examples 411 and 412: Preparation of8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-oneand6-bromo-8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-one

Step 1:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylic acid

To a solution of 1-tert-butyl 2-methyl3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-1,2-dicarboxylate (1.0g, 2.58 mmol) in ethanol:water mixture (20 mL, 1:1) was added lithiumhydroxide monohydrate (1.08 g, 25.82 mmol) the reaction mixture wasstirred at 100° C. for 4 h. Ethanol present in the reaction mixture wasevaporated, the resulting solution was diluted with water (20 mL) andneutralized with glacial acetic acid at 0° C. The obtained solid wasfiltered and dried to afford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylic acid(0.69 g, 97.9% yield) as off-white solid. Calculated (M−H): 272.04;Found (M−H): 272.0

Step 2:

Preparation of N-(2,4-dimethoxybenzyl)prop-2-yn-1-amine

To a solution of 2,4-dimethoxybenzaldehyde (1.0 g, 2.58 mmol) in2,2,2-trifluoroethanol (20 mL), prop-2-yn-1-amine hydrochloride (0.33 g,3.61 mmol) was added at 40° C. and the resulting solution was stirred at40° C. for 1 h. Then sodium borohydride (0.171 g, 4.52 mmol) was addedat room temperature and reaction mixture was stirred at room temperaturefor 1 h. The reaction mixture was evaporated, the resulting residue wasdissolved in water (40 mL) and extracted with dichloromethane (2×100mL). The combined organic layer was dried over anhydrous sodium sulfate,filtered and concentrated to get the crude product which was purified bysilica gel column chromatography using 30% ethyl acetate in hexane toafford the title compound N-(2,4-dimethoxybenzyl)prop-2-yn-1-amine (0.98g, 79.7% yield) as pale yellow liquid. Calculated (M+H): 206.11; Found(M+1): 206.1

Step-3:

Preparation ofN-(2,4-dimethoxybenzyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide

To a solution of3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylic acid (0.4g, 1.46 mmol) in dichloromethane (35 mL), triethylamine (0.444 g, 4.39mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.42 g, 2.19 mmol) and N-hydroxybenzotriazole (0.22 g, 1.46 mmol) wereadded at 0° C. and the reaction mixture was stirred at 0° C. for 30 min.Then N-(2,4-dimethoxybenzyl)prop-2-yn-1-amine (0.45 g, 2.19 mmol) wasadded and the reaction mixture was stirred at room temperature for 18 h.The reaction mixture was quenched with water (30 mL) and extracted withdichloromethane (2×100 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to get crudeproduct, which was purified by silica gel column chromatography using30% ethyl acetate in hexane to afford the title compoundN-(2,4-dimethoxybenzyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide(0.60 g, 89.5% yield) as yellowish gum. Calculated (M+H): 461.14; Found(M+1): 461.1.

Step-4:

Preparation of2-(2,4-dimethoxybenzyl)-8-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-oneand2-(2,4-dimethoxybenzyl)-8-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methylene-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one

To a solution ofN-(2,4-dimethoxybenzyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide(0.6 g, 1.30 mmol) in N,N-dimethylformamide (4 mL),1,8-diazabicycloundec-7-ene (0.19 mL, 1.30 mmol) was added and thereaction mixture was stirred under microwave irradiation at 120° C. for10 min. The reaction mixture was diluted with ethyl acetate (60 mL) andwashed with ice cold water (2×50 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and evaporated to get crude mixture(0.6 g). The crude mixture was as such taken for next step withoutpurification. Calculated (M+H): 461.14; Found (M+1): 461.1.

Step-5:

Preparation of8-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-one

To a solution of crude mixture of2-(2,4-dimethoxybenzyl)-8-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-oneand2-(2,4-dimethoxybenzyl)-8-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methylene-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one(0.6 g, 1.30 mmol) in trifluoroacetic acid (4 mL), triethylsilane (1.25mL, 7.82 mmol) was added and the reaction mixture was stirred undermicrowave irradiation at 120° C. for 30 minutes. The reaction mixturewas evaporated to get the crude compound which was purified by silicagel column chromatography using 50% ethyl acetate in hexane to affordthe title compound8-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-oneas off-white solid (0.25 g, 62.5% yield). Calculated (M+H): 311.07;Found (M+1): 311.1.

Step-6:

Preparation of8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-one

To a suspension of8-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-one(0.25 g, 0.81 mmol) in acetone (20 mL), potassium carbonate (0.33 g,2.42 mmol) and 2-chloro-1-(3-fluoropyrrolidin-1-yl)ethanone (0.20 g,1.21 mmol) were added and the reaction mixture was stirred at 55° C. for8 h. The reaction mixture was filtered and the filtrate was evaporatedto get crude product which was purified by silica gel columnchromatography using 3% methanol in dichloromethane to afford titlecompound8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-one(0.29 g, 81.9% yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.11 (d, J=6.0 Hz, 1H), 7.98-7.97 (m, 1H), 7.49-7.44 (m, 2H),6.91 (d, J=2.8 Hz, 1H), 6.65 (s, 1H), 5.49-5.24 (m, 1H), 4.75-4.57 (m,2H), 3.84-3.45 (m, 4H), 2.30 (s, 3H), 2.26-2.05 (m, 2H). Calculated(M+H): 440.13; Found (M+H): 440.1. HPLC Purity: 99.08%.

Step-7:

Preparation of6-bromo-8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-one

To a stirred solution of8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-one(0.14 g, 0.32 mmol) in carbon tetrachloride (50 mL),azobisisobutyronitrile (0.005 g, 0.032 mmol) and N-bromosuccinimide wereadded at 0° C. The reaction mixture was slowly warmed to roomtemperature and stirred for 2 h. The reaction mixture was diluted withdichloromethane (50 mL) and washed with water (2×30 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedto get crude product which was purified by silica gel columnchromatography using 70% ethyl acetate in hexane and further purified bypreparative HPLC (analytical conditions: column: chemsil C18 (250 mm×4.6mm×5μ), mobile phase (A): 0.1% ammonia in water, mobile phase (B):acetonitrile, flow rate: 1.0 mL/min, T/% B: 0/20, 10/80, 25/90, 27/20,30/20) to afford title compound6-bromo-8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-4methylpyrrolo[1,2-a]pyrazin-1(2H)-one (0.015 g, 9.1% yield) as off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.92 (d, J=6.8 Hz, 1H), 7.85(brs, 1H), 7.47 (t, J=9.6 Hz, 1H), 6.98 (s, 1H), 6.60 (s, 1H), 5.50-5.20(m, 1H), 4.66-4.51 (m, 2H), 3.76-3.31 (m, 4H), 2.62 (s, 3H), 2.30-1.90(m, 2H). Calculated (M+H): 518.04; Found (M+H): 518.0. HPLC Purity:99.32%.

TABLE 45 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC name Analytical data 413

8-(3,4- dichlorophenyl)-2- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)-4-methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm): 8.01 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H),7.48 (d, J = 1.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.66 (s, 1H),5.49-5.24 (m, 1H), 4.75-4.57 (m, 2H), 3.87-3.39 (m, 4H), 2.29 (s, 3H),2.21-1.95 (m, 2H). Calculated (M + H): 422.08; Found (M + H): 422.2.HPLC Purity: 98.57% 414

8-(3-chloro-4- fluorophenyl)-2- (2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR (400MHz, DMSO- d₆) δ (ppm): 7.94 (dd, 1.6 Hz, J = 7.6 Hz, 1H), 7.66-7.63 (m,1H), 7.46 (d, J = 4.2 Hz, 1H), 7.36 (t, J = 8.8 Hz, 1H), 6.86 (d, J =4.2 Hz, 1H), 6.65 (s, 1H), 5.49-5.24 (m, 1H), 4.75- 4.56 (m, 2H),3.84-3.23 (m, 4H), 2.28 (s, 3H), 2.21-2.05 (m, 2H). Calculated (M + H):406.11; Found (M + H): 406.1. HPLC Purity: 99.23% 415

6-bromo-8-(3- chloro-4- fluorophenyl)-2- (2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR (400MHz, DMSO- d₆) δ (ppm): 7.75 (dd, J = 2.4 Hz, 7.6 Hz, 1H), 7.53-7.49 (m,1H), 7.36 (t, J = 8.8 Hz, 1H), 6.92 (s, 1H), 6.60 (s, 1H), 5.48-5.24 (m,1H), 4.69-4.51 (m, 2H), 3.81-3.23 (m, 4H), 2.62 (s, 3H), 2.31-2.05 (m,2H). Calculated (M + H): 484.02; Found (M + H): 484.0. HPLC Purity:100.0% 416

8-(3-chloro-4- fluorophenyl)-2- (2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)-4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR (400MHz, DMSO- d₆) δ (ppm): 7.93 (dd, J = 2 Hz, 7.2 Hz, 1H), 7.67-7.63 (m,1H), 7.46 (d, J = 2.8 Hz, 1H), 7.36 (t, J = 8.8 Hz, 1H), 6.86 (d, J =3.2 Hz, 1H), 6.63 (s, 1H), 4.47 (s, 2H), 4.39-4.26 (m, 2H), 3.96 (d, J =19.6 2H), 2.28 (s, 3H), 1.58 (d, J = 22 Hz, 3H). Calculated (M + H):406.11; Found (M + H): 406.1. HPLC purity: 99.89% 417

8-(3-chloro-4- fluorophenyl)-2- (2-(3,3- difluoroazetidin-1-yl)-2-oxoethyl)-4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR (400MHz, DMSO- d₆) δ (ppm): 7.93 (d, J = 7.2 Hz, 1H), 7.65 (brs, 1H), 7.46(s, 1H), 7.36 (t, J = 9.2 Hz, 1H), 6.86 (s, 1H), 6.63 (s, 1H), 4.71-4.68(m, 2H), 4.53 (s, 2H), 4.35-4.32 (m, 2H), 2.29 (s, 3H). Calculated (M +H): 410.08; Found (M + H): 410.1. HPLC purity: 99.05% 418

8-(3-chloro-4- fluorophenyl)-2- (2-(3-ethyl-3- fluoroazetidin-1-yl)-2-oxoethyl)-4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR (400MHz, DMSO- d₆) δ (ppm): 7.93 (dd, J = 2.4 Hz, 7.6 Hz, 1H), 7.66-7.62 (m,1H), 7.45 (d, J = 2.8 Hz, 1H), 7.36 (t, J = 9.2 Hz, 1H), 6.85 (d, J =2.4 Hz, 1H), 6.63 (s, 1H), 4.51-4.42 (m, 2H), 4.37- 4.25 (m, 2H),4.01-3.87 (m, 2H), 2.28 (s, 3H), 1.92-1.81 (m, 2H), 0.91 (t, J = 7.6 Hz,3H). Calculated (M + H): 420.12; Found (M + H): 420.1. HPLC purity:99.20% 419

8-(3,4- dichlorophenyl)-2- (2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)-4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.57(d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 6.89 (s. 1H), 6.65 (s, 1H), 4.47 (s,2H), 4.39-4.26 (m, 2H), 3.96 (d, J = 19.6 Hz, 2H), 2.29 (s, 3H), 1.59(d, J = 22.4 Hz, 3H). Calculated (M + H): 422.28, Found (M + H): 422.1,HPLC purity: 99.85% 420

8-(5,6- dichloropyridin-3- yl)-2-(2-(3-fluoro- 3-methylazetidin-1-yl)-2-oxoethyl)- 4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR(400 MHz, DMSO- d₆) δ (ppm); 8.66 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 2.0Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.69 (s,1H), 4.53-4.48 (m, 2H), 4.45-4.29 (m, 2H), 4.02-3.94 (m, 2H), 2.30 (s,3H), 1.58 (d, J = 22 Hz, 3H). Calculated (M + H): 423.07; Found (M + 1):423.0. HPLC purity 99.55% 421

8-(5,6- dichloropyridin-3- yl)-2-(2-(3-fluoro- 3- (fluoromethyl)azetidin-1-yl)-2- oxoethyl)-4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one¹H NMR (400 MHz, DMSO- d₆) δ (ppm); 8.66 (d, J = 2.4 Hz, 1H), 8.50 (d, J= 1.6 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H), 7.03 (d, J = 3.2 Hz, 1H), 6.69(s, 1H), 4.89-4.71 (m, 2H), 4.52-4.36 (m, 4H), 4.13-3.96 (m, 2H), 2.30(s, 3H). Calculated (M + H): 441.06; Found (M + 1): 437.0. HPLC purity99.52% 422

8-(5,6- dichloropyridin-3- yl)-2-(2-(3-ethyl- 3-fluoroazetidin-1-yl)-2-oxoethyl)-4- methylpyrrolo[1,2- a]pyrazin-1(2H)- one ¹H NMR (400MHz, DMSO- d₆) δ (ppm); 8.66 (d, J = 1.6 Hz, 1H), 8.49 (d, J = 2.0 Hz,1H), 7.54 (d, J = 2.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.70 (s, 1H),4.54-4.45 (m, 2H), 4.35-4.26 (m, 2H), 4.02-3.87 (m, 2H), 2.30 (s, 3H),1.93- 1.81 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H). Calculated (M + H):437.09; Found (M + 1): 437.0. HPLC purity 99.52%

Example 423: Preparation of6-bromo-8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolo[1,2-a]pyrazin-1(2H)-one

To a solution of8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolo[1,2-a]pyrazin-1(2H)-one(0.1 g, 0.23 mmol) in carbon tetrachloride (20 mL) were addedN-bromosuccinimide (0.041 g, 0.23 mmol) and AIBN (0.004 g, 0.023 mmol)at 0° C. and the reaction mixture was stirred at 0° C. to 5° C. for 1 h.The reaction mixture was diluted with water (20 mL) and extracted withdichloromethane (2×40 mL). The organic layer was dried over anhydroussodium sulfate, filtered and concentrated to get the crude compoundwhich was purified by preparative HPLC (column: chemsil C18(250 mm×4.6mm×5μ), mobile phase (A): 0.1% ammonia in water, mobile phase (B):acetonitrile, flow rate: 1.0 mL/min, T/% B: 0/20, 10/80, 25/90, 27/20,30/20) to afford the title compound6-bromo-8-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)pyrrolo[1,2-a]pyrazin-1(2H)-one(0.015 g, 13% yield) as white solid. Calculated (M+H): 504.03; Found(M+H): 504.0. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.06 (d, J=6.4 Hz, 1H), 7.96 (bs, 1H), 7.48 (t, J=10Hz, 1H), 7.29 (d, J=5.6 Hz, 1H), 7.09 (s, 1H), 6.95-6.94 (m, 1H),5.48-5.24 (m, 1H), 4.79-4.60 (m, 2H), 3.86-3.27 (m, 4H), 2.30-1.95 (m,2H). HPLC purity: 97.37%.

O. Preparation of Imidotriazinones Example 424: Preparation of5-(3-chloro-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

Step-1:

Preparation of ethyl 1H-imidazole-5-carboxylate

To a stirred solution of 1H-imidazole-5-carboxylic acid (0.2 g, 1.78mmol) in ethanol (10 mL) was added sulfuric acid (0.48 mL, 8.92 mmol)and the reaction mixture was refluxed for 16 h. The reaction mixtureconcentrated under reduced pressure. The residue was diluted with water,neutralized using saturated sodium bicarbonate solution and extractedusing ethyl acetate (2×50 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The crude productwas purified by silica gel column chromatography using 5% methanol indichloromethane to afford title compound ethyl1H-imidazole-5-carboxylate (0.08 g, 32.0% yield) as an off-white solid.Calculated (M+H): 141.06, Found (M+H): 141.0.

Step-2:

Preparation of ethyl 1-amino-1H-imidazole-5-carboxylate

To stirred solution of ethyl 1H-imidazole-5-carboxylate (0.1 g, 0.71mmol) in N,N-dimethylformamide (10 mL) cooled to −10° C., was addedlithium bis(trimethylsilyl)amide (0.78 mL, 0.78 mmol) drop wise and thereaction mixture was stirred at −10° C. for 15 min. Then(aminooxy)diphenylphosphine oxide (0.199 g, 0.85 mmol) was added at −10°C. and the reaction mixture was stirred at room temperature for 6 h. Thereaction mixture was quenched by slow addition of water until theprecipitate formed was dissolved to become clear solution. Then it wasextracted using ethyl acetate (2×50 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated to affordthe title compound ethyl 1-amino-1H-imidazole-5-carboxylate as off whitesolid (0.1 g, crude). Calculated (M+H): 156.07; Found (M+H): 156.1.

Step-3:

Preparation of imidazo[5,1-f][1,2,4]triazin-4(3H)-one

To a solution of ethyl 1-amino-1H-imidazole-5-carboxylate (0.38 g, 2.44mmol) in ethanol (20 mL) was added formamidine acetate (1.27 g, 12.25mmol) and the reaction mixture was heated at 85° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was cooled to roomtemperature and the solid obtained was filtered, washed with hexane anddried under high vacuum to afford the title compoundimidazo[5,1-f][1,2,4]triazin-4(3H)-one (0.17 g, crude) as a off-whitesolid. Calculated (M+H): 137.04; Found (M+H): 137.1.

Step-4:

Preparation of 5-bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one

To a solution of imidazo[5,1-f][1,2,4]triazin-4(3H)-one (0.1 g, 0.73mmol) in N,N-dimethylformamide (25 mL), was added N-bromosuccinimide(0.131 g, 0.7347 mmol) at −20° C. and the reaction was stirred at thesame temperature for 20 min. After completion of the reaction, thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (2×60 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated to afford the crude compound.Addition of ethyl acetate (10 mL) to the crude compound resulted in theprecipitation of the product. The precipitated product was filtered,washed with ethyl acetate and dried under high vacuum to afford5-bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one (0.07 g, 44.3% yield) asoff white solid. Calculated (M+H): 214.95;

Found (M+H): 215.0.

Step-5:

Preparation of5-bromo-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

To a stirred solution of2-(5-bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one (0.25 g, 1.18 mmol) inacetone (30 mL) were added potassium carbonate (0.492 g, 2.37 mmol) and2-chloro-1-(3-fluoro-3-methylazetidin-1-yl)ethanone (0.393 g, 3.56 mmol)at room temperature. The reaction mixture was heated at 70° C. for 16 h.After the completion of the reaction, the reaction mixture was filteredand the filtrate was concentrated. The crude product was purified bysilica gel column chromatography using 80% ethyl acetate in hexane toafford the title compound5-bromo-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one(0.07 g, 25.7% yield) as off white solid. Calculated (M+H): 344.01,Found (M+H): 344.0.

Step-6:

Preparation of5-(3-chloro-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

To a stirred solution of5-bromo-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one(0.07 g, 0.20 mmol) in 1,4-dioxane:water mixture (25 mL, 4:1), wereadded (3-chloro-4-fluorophenyl)boronic acid (0.043 g, 0.24 mmol) andpotassium carbonate (0.084 g, 0.610 mmol) and the reaction mixture waspurged with argon for 20 min. Then1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.008 g, 0.010 mmol) was added at roomtemperature and the reaction mixture was heated at 100° C. for 3 h.After the completion of the reaction, the reaction mixture was cooled toroom temperature, filtered and the filtrate was concentrated. The crudeproduct was purified by silica gel column chromatography using 90% ethylacetate in hexane to afford the title compound5-(3-chloro-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one(0.02 g, 25.3% yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.61 (s, 1H), 8.58 (d, J=7.6 Hz, 1H), 8.31-8.28 (m, 1H), 8.09 (s,1H), 7.49 (t, J=9.2 Hz, 1H), 4.63 (s, 2H), 4.45-4.31 (m, 2H), 4.07-3.99(m, 2H), 1.61 (d, J=22.0 Hz, 3H). Calculated (M+H): 394.08; Found (M+H):394.1; HPLC purity: 99.42%.

TABLE 46 The following compounds were prepared by the method describedabove: Ex. No. Structure Name Analytical data+HZ,1/536 425

5-(3,4-dichlorophenyl)-3- (2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)imidazo[5,1- f][1,2,4]triazin-4(3H)- one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm); 8.63 (s, 2H), 8.29-8.27 (m, 1H), 8.10 (s, 1H), 7.71 (d, J =8.4 Hz, 1H), 4.64 (s, 2H), 4.47-4.31 (m, 2H), 4.07-3.99 (m, 2H), 1.61(d, J = 22 Hz, 3H). Calculated (M + H): 410.05; Found (M + 1): 410.0.HPLC purity 98.23%

P. Preparation of Imidazopyrazinones Example 426: Preparation of1-(3-chloro-4-fluorophenyl)-7-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-3-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step-1:

Preparation of (3-chloropyrazin-2-yl)methanamine hydrochloride

To a solution of 3-chloropyrazine-2-carbonitrile (10 g) in acetic acid(100 mL) was added Raney Nickel (50% slurry in water, 10 g). Theresulting mixture was stirred under 4 bar hydrogen pressure at roomtemperature for 15 h. The reaction mixture was filtered through celiteand the filtrate was concentrated under reduced pressure andco-evaporated with toluene. The remaining brown solid was dissolved inethyl acetate at 50° C. and cooled on an ice-bath. 4M hydrochloric acidin dioxane (50 mL) was added and the reaction mixture was allowed tostir at room temperature for 18 h. The precipitate formed was collectedby filtration, washed with diethyl ether and dried under reducedpressure. The product brown solid obtained was dissolved in methanol at60° C. and filtered. The filtrate was partially concentrated, cooled toroom temperature and diethyl ether (500 mL) was added. The mixture wasallowed to stir at room temperature 18 h. The solids formed werecollected by filtration, washed with diethyl ether and dried underreduced pressure to afford the title compound(3-chloropyrazin-2-yl)methanamine hydrochloride (7.67 g, crude) as abrown solid. Calculated (M+H): 144.03; Found (M+H): 144.0.

Step-2:

Preparation N-((3-chloropyrazin-2-yl)methyl)acetamide

To a solution of (3-chloropyrazin-2-yl)methanamine hydrochloride (3.5 g,19.49 mmol) in dichloromethane (100 mL) was added diisopropylethylamine(10.18 mL, 38.99 mmol) followed by acetic anhydride (3.67 mL, 38.9 mmol)at room temperature. Then the reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was diluted with ice water(100 mL), basified with saturated sodium bicarbonate solution andextracted with ethyl acetate (3×200 mL). The combined organic layer wasdried over anhydrous sodium sulphate, filtered and concentrated. Thecrude product was purified by silica gel column chromatography using 3%methanol in dichloromethane to afford the title compoundN-((3-chloropyrazin-2-yl)methyl)acetamide (1.66 g, 46% yield) as a brownsolid. Calculated (M+H): 186.0; Found (M+H): 186.1.

Step-3:

Preparation of 8-chloro-3-methylimidazo[1,5-a]pyrazine

To a solution of N-((3-chloropyrazin-2-yl)methyl)acetamide (1.66 g, 8.97mmol) in acetonitrile (30 mL) and N,N-dimethylformamide (0.6 mL), wasadded phosphorous oxychloride (2.5 mL, 26.9 mmol) and the reactionmixture was stirred at 60° C. for 18 h. Then the solvent was removedunder pressure, the resulting residue was basified with saturated sodiumbicarbonate solution and extracted with ethyl acetate (3×100 mL). Thecombined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated. The crude product was purified by silica gelcolumn chromatography using 4% methanol in dichloromethane to afford thetitle compound 8-chloro-3-methylimidazo[1,5-a]pyrazine (1.45 g, 97%yield) as a yellow solid. Calculated (M+H): 168.0; Found (M+H): 168.1.

Step-4:

Preparation of 1-bromo-8-chloro-3-methylimidazo[1,5-a]pyrazine

To a solution of 8-chloro-3-methylimidazo[1,5-a]pyrazine (1.45 g, 8.68mmol) in N,N-dimethylformamide (30 mL), was added N-bromosuccinimide(1.54 g, 8.68 mmol) and the reaction mixture was stirred at roomtemperature for 30 min. Then the reaction mixture was diluted with water(50 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayer was dried over anhydrous sodium sulphate, filtered andconcentrated. The crude product was purified by silica gel columnchromatography using 1% methanol in dichloromethane to afford the titlecompound 1-bromo-8-chloro-3-methylimidazo[1,5-a]pyrazine (1.06 g, 79%yield) as a yellow solid. Calculated (M+H): 245.9; Found (M+H): 246.0.

Step-5:

Preparation of 1-bromo-3-methylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of 1-bromo-8-chloro-3-methylimidazo[1,5-a]pyrazine (1.06g) in tetrahydrofuran (10 mL), was added 6N aqueous hydrochloric acid(25 mL) and the reaction mixture was stirred at 60° C. for 1 h. Then thereaction mixture was concentrated and dried to afford the title compound1-bromo-3-methylimidazo[1,5-a]pyrazin-8(7H)-one (0.82 g, 83% yield) as awhite solid. Calculated (M+H): 227.9; Found (M+H): 228.0.

Step-6:

Preparation of ethyl2-(1-bromo-3-methyl-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)acetate

To a stirred solution 1-bromo-3-methylimidazo[1,5-a]pyrazin-8(7H)-one(0.3 g, 1.32 mmol) in dry acetone (15 mL) was added potassium carbonate(0.54 g, 3.96 mmol) followed by ethyl 2-bromoacetate (0.29 mL, 2.64mmol) at room temperature and the reaction mixture was heated at refluxfor 18 h. The reaction mixture was filtered and the filtrate wasconcentrated. The crude product was purified by silica gel columnchromatography using 2% methanol in dichloromethane to afford the titlecompound ethyl2-(1-bromo-3-methyl-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)acetate (0.37 g,89% yield) as a white solid. Calculated (M+H): 314.0; Found (M+H):314.0.

Step-7:

Preparation of2-(1-(3-chloro-4-fluorophenyl)-3-methyl-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)aceticacid

To a solution of ethyl2-(1-bromo-3-methyl-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)acetate (0.37 g,1.18 mmol) and (3-chloro-3-fluoro-phenyl)boronic acid (0.267 g, 1.53mmol) in 1,4-dioxane:water mixture (20 mL, 4:1), potassium carbonate(0.49 g, 3.54 mmol) was added. The reaction mixture was purged withargon for 15 min,1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex [Pd(dppf)Cl₂.DCM] (0.048 g, 0.059 mmol) wasadded and the reaction mixture was stirred at 100° C. for 18 h. Thereaction mixture was diluted with water (60 mL) and washed with ethylacetate (2×30 mL). The aqueous layer was separated, acidified with 1.5Mhydrochloric acid solution and extracted with ethyl acetate (3×60 mL).The combined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated to afford the title compound2-(1-(3-chloro-4-fluorophenyl)-3-methyl-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)aceticacid (0.22 g, 55% yield) as off-white solid. Calculated (M+H): 336.0;Found (M+H): 336.1.

Step-8:

Preparation1-(3-chloro-4-fluorophenyl)-7-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-3-methylimidazo[1,5-a]pyrazin-8(7H)-one

To a stirred solution of2-(1-(3-chloro-4-fluorophenyl)-3-methyl-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)aceticacid (0.11 g, 0.32 mmol) and 3-fluoro-3-methylazetidine hydrochloride(0.082 g, 0.65 mmol) in dichloromethane (15 mL) was added triethylamine(0.36 mL, 2.62 mmol) and the reaction mixture was cooled to 0° C. Then1-propanephosphonic anhydride solution (T₃P) (0.35 mL, 0.55 mmol, 50% inethyl acetate) was added and the reaction mixture was stirred at roomtemperature for 12 h. The solution was diluted with water and extractedwith dichloromethane (3×30 mL). The combined organic layer was driedover anhydrous sodium sulfate, filtered and concentrated to get thecrude compound. The crude product was purified by preparative HPLC(analytical conditions: column: chemsil C₁₈ (250 mm×4.6 mm×5 mic),mobile phase (A): 0.1% ammonia in water, mobile phase (B): acetonitrile,flow rate: 1.0 mL/min, T/% B: 0/20, 10/80, 25/90, 27/20, 30/20) toafford the title compound1-(3-chloro-4-fluorophenyl)-7-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-3-methylimidazo[1,5-a]pyrazin-8(7H)-one(0.022 g, 16% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.59 (dd, J₁=2 Hz, 7.6 Hz, 1H), 8.29-8.25 (m, 1H), 7.42 (t, =9.2Hz, 1H), 7.35 (d, J=6 Hz, 1H), 6.86 (d, =6 Hz, 1H), 4.53 (s, 2H);4.38-4.30 (m, 2H), 4.01 (d, J=19.2 Hz, 2H), 2.55 (s, 3H), 1.63 (d, J=22Hz, 3H). Calculated (M+H): 407.1, Found (M+H): 407.1. HPLC purity:99.71%.

The following compounds were prepared by the method described above:

The following compounds were prepared by the method described above: Ex.No. Structure IUPAC Name Analytical Data 427

1-(4-fluoro-3- (trifluoromethyl) phenyl)-7-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-3- methylimidazo[1,5- a]pyrazin-8(7H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.80 (d, J = 6.8 Hz, 1H), 8.62 (s , 1H), 7.52 (t,J = 10 Hz, 1H), 7.36 (d, J = 6 Hz, 1H), 6.87 (s, 1H), 5.38-5.2 (m, 1H),4.77-4.63 (m, 2H), 3.79- 3.58 (m, 4H), 2.56 (s, 3H), 2.30-1.96 (m, 2H),Calculated (M + H): 441.1; Found (M + H): 441.1. HPLC purity: 99.13% 428

1-(3-chloro-4- fluorophenyl)-7-(2- (3-fluoropyrrolidin-1-yl)-2-oxoethyl)-3- methylimidazo[1,5- a]pyrazin-8(7H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.60 (d, J = 7.6 Hz, 1H), 8.28-8.25 (m, 1H), 7.41(t, J = 12 Hz, 1H), 7.35 (d, J = 6 Hz, 1H), 6.87 (t, J = 2.8 Hz, 1H),5.50-5.25 (m, 1H), 4.80- 4.61 (m, 2H), 3.87-3.48 (m, 4H), 2.54 (s, 3H),2.30-1.96 (m, 2H), Calculated (M + H): 407.1; Found (M + H): 407.1. HPLCpurity: 99.36% 429

1-(3,4- dichlorophenyl)-7- (2-(3- fluoropyrrolidin-1- yl)-2-oxoethyl)-3-methylimidazo[1,5- a]pyrazin-8(7H)-one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.67 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H),7.36 (d, J = 5 .6 Hz, 1H), 6.89-6.87 (m, 1H), 5.51- 5.25 (m, 1H),4.81-4.61 (m, 2H), 3.88-3.49 (m, 4H), 2.55 (s, 3H), 2.30-2.08 (m, 2H).Calculated (M + H): 423.0; Found (M + H): 423.1. HPLC purity: 99.05% 430

1-(3-chloro-4- fluorophenyl)-7-(2- (3,3- difluoroazetidin-1-yl)-2-oxoethyl)-3- methylimidazo[1,5- a]pyrazin-8(7H)-one ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.59 (d, J = 7.6 Hz, 1H), 8.28-8.25 (m, 1H), 7.42(t, J = 8.8 Hz, 1H), 7.35 (d, J = 6 Hz 1H), 6.85 (d, J = 5.6 Hz, 1H),4.73 (t, J = 11.2 Hz, 2H), 4.60 (s, 2H), 4.35 (t, J = 12 Hz, 2H), 2.55(s, 3H), Calculated (M + H): 411.0; Found (M + H): 411.1. HPLC purity:96.7% 431

1-(3-chloro-4- fluorophenyl)-7-(2- (3-ethyl-3- fluoroazetidin-1-yl)-2-oxoethyl)-3- methylimidazo[1,5- a]pyrazin-8(7H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.59 (d, J = 6.8 Hz, 1H), 8.26 (brs, 1H), 7.41 (t, J =9.2 Hz, 1H), 7.34 (d, J = 5.6 Hz, 1H), 6.85 (d, J = 6.4 Hz, 1H), 4.53(s, 2H), 4.36-4.30 (m, 2H), 4.01-3.92 (m, 2H), 2.54(s, 3H), 1.92-1.85(m, 2H), 0.92 (t, J = 7.2 Hz, 3H), Calculated (M + H): 421.1; Found (M +H): 421.1. HPLC purity: 96.71%

Example 432: Preparation of1-(3-chloro-4-fluorophenyl)-3-cyclopropyl-7-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one

Step-1:

Preparation of (3-chloropyrazin-2-yl)methanamine

To a solution of 3-chloropyrazine-2-carbonitrile (2 g) in acetic acid(20 mL) was added Raney nickel (50% slurry in water, 1.6 g). Theresulting mixture was stirred under 4 bar hydrogen pressure at roomtemperature for 15 h. The reaction mixture was filtered through celiteand the filtrate was concentrated under reduced pressure andco-evaporated with toluene to afford the title compound(3-chloropyrazin-2-yl)methanamine acetate (2.9 g, crude) as brown solid.Calculated (M+H): 144.03; Found (M+H): 144.0.

Step-2:

Preparation of N-((3-chloropyrazin-2-yl)methyl)cyclopropanecarboxamide

To a solution of (3-chloropyrazin-2-yl)methanamine (5.0 g, 24.63 mmol)in dichloromethane (50 mL) was added diisopropylethylamine (13.26 mL,73.89 mmol) followed by cyclopropanecarbonyl chloride (4.46 mL, 49.26mmol). Then the reaction mixture was stirred at room temperature for 1h. The reaction mixture was diluted with ice water (100 mL), basifiedwith sodium bicarbonate solution and extracted with ethyl acetate (3×100mL). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated. The crude product was purified bysilica gel column chromatography using 2% methanol in dichloromethane toafford the title compoundN-((3-chloropyrazin-2-yl)methyl)cyclopropanecarboxamide (2.5 g, 47%yield) as brown solid. Calculated (M+H): 212.05; Found (M+H): 212.1.

Step-3:

Preparation of 8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine

To a solution of N-((3-chloropyrazin-2-yl)methyl)cyclopropanecarboxamide(2.5 g, 12.32 mmol) in acetonitrile (80 mL) and N,N-dimethylformamide(0.5 mL), was added phosphorous oxychloride (3.4 mL, 36.96 mmol) and thereaction mixture was stirred at 60° C. for 2 h. Then the solvent wasremoved under pressure, the resulting crude mixture was basified withsodium bicarbonate solution and extracted with ethyl acetate (3×100 mL).The combined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated. The crude product was purified by silica gelcolumn chromatography using 3% methanol in dichloromethane to afford thetitle compound 8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine (1.65 g, 68%yield) as pale yellow solid. Calculated (M+H): 194.04; Found (M+H):194.1.

Step-4:

Preparation of 1-bromo-8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine

To a solution of 8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine (1.65 g,8.54 mmol) in N,N-dimethylformamide (50 mL), was addedN-bromosuccinimide (1.54 g, 8.54 mmol) and the reaction mixture wasstirred at room temperature for 30 min. Then the reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated. The crude product was purified by silica gelcolumn chromatography using 30% ethyl acetate in hexane afford the titlecompound 1-bromo-8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine (1.6 g,69.0% yield) as white solid. Calculated (M+H): 271.95; Found (M+H):272.0.

Step-5:

Preparation of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of 1-bromo-8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine(1.6 g, 5.90 mmol) in tetrahydrofuran (15 mL), was added 6N hydrochloricacid (50 mL) and the reaction mixture was stirred at 60° C. for 2 h.Then the reaction mixture was diluted with water (50 mL), basified withsodium bicarbonate solution and extracted with ethyl acetate (3×70 mL).The combined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated to afford the title compound1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one (1.62 g, 99% yield)as brown solid. Calculated (M+H): 253.9; Found (M+H): 254.1.

Step-6:

Preparation of1-bromo-3-cyclopropyl-7-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one

To a stirred solution of1-bromo-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one (0.35 g, 1.35 mmol)in dry acetone (30 mL) was added potassium carbonate (0.57 g, 4.18 mmol)followed by 2-chloro-1-(pyrrolidin-1-yl)ethanone (0.27 g, 1.67 mmol) atroom temperature and the reaction mixture was heated at 60° C. for 18 h.The reaction mixture was filtered and the filtrate was concentratedunder vacuum. The crude product was purified by silica gel columnchromatography using 2% methanol in dichloromethane to afford the titlecompound1-bromo-3-cyclopropyl-7-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one(045 g, 84% yield) as pale yellow solid. Calculated (M+H): 383.04; Found(M+H): 383.2.

Step-7:

Preparation of1-(3-chloro-4-fluorophenyl)-3-cyclopropyl-7-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of1-bromo-3-cyclopropyl-7-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one(015 g, 0.9 mmol) and (3-chloro-3-fluoro-phenyl)boronic acid (0.09 g,0509 mmol) in 1,4-dioxane:water mixture (20 mL, 4:1), potassiumcarbonate (0.16 g, 1.17 mmol) was added. The reaction mixture was purgedwith argon for 15 min and1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (Pd(dppf)Cl₂.DCM) (0.03 g, 0.039 mmol) wasadded. Then the reaction mixture was stirred at 100° C. for 4 h. Thereaction mixture was diluted with water (30 mL) and extracted with ethylacetate (3×50 mL). The combined organic layer was dried over anhydroussodium sulphate, filtered and concentrated. The crude product waspurified by silica gel column chromatography using 2% methanol indichloromethane to afford the title compound1-(3-chloro-4-fluorophenyl)-3-cyclopropyl-7-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one(0.041 g, 24% yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.54 (d, =6.8 Hz, 1H), 8.23-8.23 (m, 1H), 7.57 (d, J=6.0 Hz, 1H),7.40 (t, J=9.2 Hz, 1H), 6.89-6.87 (m, 1H), 5.50-4.79 (m, 1H), 4.79-4.61(m, 2H), 3.87-3.30 (m, 4H), 2.40-1.94 (m, 3H), 1.08-1.03 (m, 4H).Calculated (M+H): 433.12; Found (M+H): 433.1. HPLC purity: 99.7%.

Ex. No. Structure IUPAC Name Analytical Data 433

3-cyclopropyl-1-(3,4- dichlorophenyl)-7-(2- (3-fluoropyrrolidin-1-yl)-2- oxoethyl)imidazo[1,5- a]pyrazin-8(7H)-one ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.62 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.62-7.58 (m,2H), 6.90-6.88 (m, 1H), 5.51- 5.25 (m, 1H), 4.80-4.65 (m, 2H), 3.88-3.39(m, 4H), 2.36- 1.97 (m, 3H), 1.08-1.03 (m, 4H). (M + H): 449.09; Found(M + H): 449.1:, HPLC purity: 98.68% 434

3-cyclopropyl-1-(4- fluoro-3- (trifluoromethyl)phenyl)- 7-(2-(3-fluoropyrrolidin-1-yl)- 2- oxoethyl)imidazo[1,5- a]pyrazin-8(7H)-one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.75 (d, J = 6.8 Hz, 1H), 8.53 (s, 1H),7.59 (d, J = 5.6 Hz, 1H), 7.51 (t, J = 10.4 Hz, 1H), 6.90-6.88 (m, 1H),5.50-5.25 (m, 1H), 4.81-4.61 (m, 2H), 3.88-3.38 (m, 4H), 2.35-1.96 (m,3H), 1.21-1.04 (m, 4H), (M + H): 467.14; Found (M + H): 467.1:, HPLCpurity: 98.03% 435

3-cyclopropyl-1-(3,4- dichlorophenyl)-7-(2- (3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)imidazo[1,5- a]pyrazin-8(7H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.61 (s, 1H), 8.21 (d, J = 8 Hz, 1H),7.63-7.57 (m, 2H), 6.87 (d, J = 6 Hz, 1H), 4.54 (s, 2H), 4.41-4.28 (m,2H), 4.02- 3.97 (m, 2H), 2.32 (brs, 1H), 1.6 (d, J = 22 Hz, 3H), 1.08-1.03 (m, 4H). Calculated (M + H): 449.09, Found (M + H): 449.0, HPLCpurity: 98.33%. 436

1-(3-chloro-4- fluorophenyl)-3- cyclopropyl-7-(2-(3- fluoro-3-methylazetidin-1-yl)-2- oxoethyl)imidazo[1,5- a]pyrazin-8(7H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.53 (d, J = 7.6 Hz, 1H), 8.23-8.2 (m, 1H),7.56 (d, J = 5.6 Hz, 1H), 7.4 (t, J = 8.8 Hz, 1H), 6.86 (d, J = 6 Hz,1H), 4.53 (s, 2H), 4.41-4.28 (m, 2H), 4.01-3.96 (m, 2H), 2.33-2.3 (m,1H), 1.6 (d, J = 22 Hz, 3H), 1.08-1.03 (m, 4H). Calculated (M + H):433.12, Found (M + H): 433.1, HPLC purity: 99.52%. 437

3-cyclopropyl-1-(5,6- dichloropyridin-3-yl)- 7-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)imidazo[1,5- a]pyrazin-8(7H)-one ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 9.1 (s, 1H), 8.95 (s, 1H), 7.63 (d, J = 5.6Hz, 1H), 6.92 (d, J = 5.6 Hz, 1H), 4.56 (s, 2H), 4.42-4.29 (m, 2H),4.02-3.97 (m, 2H), 2.34-2.31 (m, 1H), 1.6 (d, J = 22 Hz, 3H), 1.09-1.05(m, 4H). Calculated (M + H): 450.08, Found (M + H): 450.2, HPLC purity:99.12%. 438

3-cyclopropyl-1-(4- fluoro-3- (trifluoromethyl)phenyl)-7-(2-(3-fluoro-3- methylazetidin-1-yl)-2- oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.76 (d, J = 6.8Hz, 1H), 8.52 (brs, 1H), 7.58 (d, J = 6 Hz, 1H), 7.51 (t, J = 10 Hz,1H), 6.87 (d, J = 6.4 Hz, 1H), 4.54 (s, 2H), 4.42-4.28 (m, 2H),4.01-3.96 (m, 2H), 2.33-2.31 (m, 1H), 1.59 (d, J = 22 Hz, 3H), 1.08-1.04(m, 4H). Calculated (M + H): 467.14, Found (M + H): 467.3, HPLC purity:99.63%. 439

1-(3-chloro-4- fluorophenyl)-3- cyclopropyl-7-(2-(3- fluoro-3-(fluoromethyl)azetidin- 1-yl)-2- oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm); 8.53 (d, J = 6.0Hz, 1H), 8.21 (s, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.40 (t, J = 8.8 Hz,1H), 6.85 (d, J = 5.6 Hz, 1H), 4.90-4.72 (m, 2H), 4.55 (s, 2H),4.51-4.40 (m, 2H), 4.15-4.01 (m, 2H), 1.08-1.03 (m, 4H). 1H was mergedwith DMSO residual peak. Calculated (M + H): 451.11; Found (M + 1):451.0. HPLC purity 99.09% 440

3-cyclopropyl-1-(3,4- dichlorophenyl)-7-(2- (3-fluoro-3-(fluoromethyl)azetidin- 1-yl)-2- oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one ¹H NMR (400 MHz, DMSO-d₆) δ (ppm); 8.61 (s, 1H),8.21 (d, J = 8.8 Hz, 1H), 7.63-7.58 (m, 2H), 6.87 (d, J = 6 Hz, 1H),4.90-4.72 (m, 2H), 4.56 (s, 2H), 4.51-4.37 (m, 2H), 4.15-3.98 (m, 2H),2.33-2.31 (m, 1H), 1.08-1.03 (m, 4H). Calculated (M + H): 467.08; Found(M + 1): 467.1. HPLC purity 99.64% 441

1-(5-chloro-6- fluoropyridin-3-yl)-3- cyclopropyl-7-(2-(3- fluoro-3-methylazetidin-1-yl)-2- oxoethyl)imidazo[1,5- a]pyrazin-8(7H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.96 (d, J = 7.6 Hz, 1H), 8.89 (s, 1H), 7.62(d, J = 6.4 Hz, 1H), 6.91 (d, J = 6 Hz, 1H), 4.54 (s, 2H), 4.41-4.28 (m,2H), 4.04 (d, J = 12 Hz, 2H), 2.48-2.30 (m, 1H), 1.62 (d, J = 22 Hz,3H), 1.09-1.04 (m, 4H). Calculated (M + H): 434.1; Found (M + H): 434.0.HPLC purity: 97.07% 442

3-cyclopropyl-7-(2-(3- fluoro-3- methylazetidin-1-yl)-2-oxoethyl)-1-(4-fluoro- 3- methylphenyl)imidazo [1,5-a]pyrazin-8(7H)- one¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.08-8.02 (m, 2H), 7.53 (d, J = 6 Hz,1H), 7.10 (t, J = 8.8 Hz, 1H), 6.82 (d, J = 5.6 Hz, 1H), 4.50 (s, 2H),4.40- 4.26 (m, 2H), 4.00 (d, J = 19.6 Hz, 2H), 2.48-2.27(m, 1H), 2.24(s, 3H), 1.62 (d, J = 22 Hz, 3H), 1.06-1.01 (m, 4H). Calculated (M + H):413.1; Found (M + H): 413.0. HPLC purity: 99.51% 443

1-(4-chloro-3- methylphenyl)-3- cyclopropyl-7-(2-(3- fluoro-3-methylazetidin-1-yl)-2- oxoethyl)imidazo[1,5- a]pyrazin-8(7H)-one ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.16 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.55(d, J = 6.4 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 6 Hz, 1H)4.51 (s, 2H), 4.40-4.26 (m, 2H), 4.04 (d, J = 12.8 Hz, 2H), 2.33-2.27(m, 4H), 1.62 (d, J = 22 Hz, 3H), 1.06-1.02 (m, 4H). Calculated (M +H): 429.1; Found (M + H): 429.0. HPLC purity: 98.99%

Example 444: Preparation of1-(3-chloro-4-fluorophenyl)-7-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 2:

Preparation of N-((3-chloropyrazin-2-yl)methyl)formamide

To a stirred solution (3-chloropyrazin-2-yl)methanamine hydrochloride(0.5 g, 2.77 mmol) in dichloromethane (20 mL) and N,N-dimethyl formamide(4 mL) were added N,N-diisopropylethylamine (0.72 mL, 4.16 mmol),1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.79 g, 4.16 mmol),1-hydroxybenzotriazole (0.37 g, 2.77 mmol), formic acid (0.135 mL, 3.60mmol) and the reaction mixture was stirred at room temperature for 18 h.After completion of the reaction, the reaction mixture was quenched withwater (50 mL) and extracted with dichloromethane (3×80 mL). The combinedorganic layer was washed with brine (40 mL), dried over anhydrous sodiumsulfate and evaporated to get the crude product. The crude product waspurified by silica gel column chromatography using 2% methanol indichloromethane to afford the title compoundN-((3-chloropyrazin-2-yl)methyl)formamide (0.21 g, 44% yield) as ayellow solid. Calculated (M+H): 172.0; Found (M+H): 172.1.

Ex. No. Structure IUPAC Name Analytical Data 445

1-(3-chloro-4- fluorophenyl)-7-(2- (3-fluoro-3- methylazetidin-1- yl)-2-oxoethyl)imidazo [1,5-a]pyrazin-8(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.59 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 8.36 (s, 1H), 8.29-8.25 (m,1H), 7.49-7.41 (m, 2H), 6.85 (d, J = 6 Hz, 1H), 4.54 (s, 2H), 4.41-4.28(m, 2H), 4.04-3.96 (m, 2H), 1.62(d, J = 22 Hz, 3H), Calculated (M + H):393.0; Found (M + H): 393.0. HPLC purity: 98.71% 446

1-(4-fluoro-3- (trifluoromethyl) phenyl)-7-(2-(3-fluoro-3-methylazetidin-1- yl)-2- oxoethyl)imidazo [1,5-a]pyrazin-8(7H)- one ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.82 (d, J = 6.8 Hz, 1H), 8.61 (brs,1H), 8.39 (s, 1H), 7.57-7.50 (m, 2H), 6.86 (d, J = 6 Hz, 1H), 4.54 (s,2H), 4.42-4.28 (m, 2H), 4.01 (d, J = 20 Hz, 2H), 1.62 (d, J = 22 Hz,3H). Calculated (M + H): 427.1; Found (M + H): 427.1. HPLC purity:99.36% 447

1-(3,4- dichlorophenyl)-7- (2-(3-fluoro-3- methylazetidin-1- yl)-2-oxoethyl)imidazo [1,5-a]pyrazin-8(7H)- one ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.67 (s, 1H), 8.38 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.51 (d, J = 5.6 Hz, 1H), 6.86 (d, J = 6 Hz, 1H), 4.54(s, 2H), 4.41- 4.28 (m, 2H), 4.01 (d, J = 19.6 Hz, 2H), 1.63 (d, J = 22Hz, 3 H), Calculated (M + H): 409.0; Found (M + H): 409.0. HPLC purity:97.88%

Q. Preparation of Imidazopyrimidinones Example 448: Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,2-c]pyrimidin-5(6H)-one

Step 1:

Preparation of 2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine

To a solution of 2,4-dichloropyrimidine (1.0 g, 6.71 mmol) in ethanol(10 mL) were added triethylamine (1.13 mL, 8.05 mmol),2,2-dimethoxyethanamine (0.87 mL, 8.05 mmol) at room temperature and thereaction mixture was stirred for 24 h. After completion of reaction, thereaction mixture was concentrated under reduced pressure to obtain crudeproduct which was purified by silica gel column chromatography using 40%ethyl acetate in hexane as eluent to obtain title compound2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine (7.2 g, 76% yield) aswhite solid. Calculated (M+H): 218.06; Found (M+1): 218.1.

Step 2:

Preparation of imidazo[1,2-c]pyrimidin-5(6H)-one

To concentrated sulfuric acid (0.66 mL, 12.43 mmol),2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine (0.9 g, 4.14 mmol) wasadded at 0° C. and the resulting mixture was heated at 70° C. for 2 h.The reaction mixture was allowed to cool to room temperature, poured onto ice water and basified with solid sodium bicarbonate. Theprecipitated product was filtered, washed with cold water and dried toobtain the title compound imidazo[1,2-c]pyrimidin-5(6H)-one (0.27 g, 48%yield) as a yellow solid. Calculated (M+H): 136.04; Found (M+1): 136.2.

Step 3:

Preparation of ethyl 2-(5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)acetate

To a mixture of imidazo[1,2-c]pyrimidin-5(6H)-one (3.8 g, 28.12 mmol)and potassium carbonate (11.66 g, 84.36 mmol) in dry acetone was addedethyl 2-bromoacetate (6.22 mL, 56.24 mmol). The resulting mixture washeated at 55° C. for 16 h. The mixture was allowed to cool to roomtemperature and filtered. The filtrate was concentrated under vacuum toafford crude product, which was purified by silica gel columnchromatography using 3.5% methanol in dichloromethane to afford thetitle compound ethyl 2-(5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)acetate(4.3 g, 69% yield) as a pale yellow solid. Calculated (M+H): 222.08;Found (M+H): 222.1.

Step 4:

Preparation of ethyl2-(3-iodo-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)acetate

To a mixture of ethyl 2-(5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)acetate(2.0 g, 9.05 mmol) and sodium acetate (2.22 g, 27.14 mmol) in methanol(50 mL) was added iodine (6.9 g, 27.14 mmol) at 0° C. The reactionmixture was allowed to warm to room temperature and stirred for 5 h. Thereaction showed the presence of starting material. Again (6.9 g, 27.14mmol) of iodine was added and stirred for 19 h. The progress of thereaction was monitored by TLC. The reaction mixture was concentratedunder vacuum. The residue was diluted with ethyl acetate (500 mL),washed with saturated solution of sodium thiosulfate (200 mL), water(200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to afford the crude product, which waspurified by silica gel column chromatography using 6% methanol indichloromethane to afford the title compound ethyl2-(3-iodo-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)acetate (1.48 g, 47%yield) as pale yellow solid. Calculated (M+H): 347.98; Found (M+1):348.0.

Step 5:

Preparation of2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)aceticacid

To a solution of ethyl2-(3-iodo-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)acetate (0.2 g, 0.58mmol) and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (0.12 g, 0.58mmol) in 1,4-dioxane:water mixture (5 mL:2 mL) potassium carbonate (0.24g, 1.73 mmol) was added. The reaction mixture was purged with argon for10 min. Then1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloridedichloromethane complex [Pd(dppf)Cl₂.DCM] (0.05 g, 0.06 mmol) was addedand the reaction mixture was heated at 100° C. for 16 h. The reactionmixture was allowed to cool to room temperature, filtered through celiteand the filtrate was concentrated. The residue was diluted with water(25 mL) and washed with ethyl acetate (20 mL). The aqueous layer wasacidified with concentrated hydrochloric acid (pH-4) and extracted withethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to afford the crudecompound, which was triturated with 50% diethyl ether in n-pentane toafford the title compound2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)aceticacid (0.11 g, 55% yield) as pale yellow solid. Calculated (M+H): 356.06;Found (M+H): 356.1.

Step 6:

Preparation of3-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,2-c]pyrimidin-5(6H)-one

To a solution of2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)aceticacid (0.08 g, 0.23 mmol) in dichloromethane (10 mL) were added3-fluoropyrrolidine hydrochloride (0.05 g, 0.45 mmol) and triethylamine(0.25 mL, 1.80 mmol) at room temperature. The reaction mixture wascooled to 0° C. and 1-propanephosphonic anhydride solution (0.3 mL, 0.45mmol, 50% solution in ethyl acetate) was added. The resulting mixturewas allowed to warm to room temperature and stirred for 16 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with dichloromethane (25 mL), washed with water (2×25 mL), brine(20 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford crude product, which was purified bysilica gel column chromatography using 3% methanol in dichloromethane aseluent to afford the title compound3-(4-fluoro-3-(trifluoromethyl)phenyl)-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,2-c]pyrimidin-5(6H)-one(0.025 g, 27% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.85-7.78 (m, 2H), 7.54-7.49 (m, 2H), 7.42-7.39 (m, 1H), 6.70 (d, J=8.0Hz, 1H), 5.48-5.23 (m, 1H), 4.86-4.67 (m, 2H), 3.85-3.32 (m, 4H),2.24-2.06 (m, 2H). Calculated (M+H): 427.11; Found (M+1): 427.1. HPLCpurity: 99.83%.

TABLE 47 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical data 449

3-(6-chloro-5- (trifluoromethyl)pyridin- 3-yl)-6-(2-(3-fluoropyrrolidin-1-yl)- 2- oxoethyl)imidazo[1,2- c]pyrimidin-5(6H)- one¹H NMR (400 MHz, DMSO- d₆) δ (ppm); 8.77(d, J = 3.2 Hz, 1H), 8.43 (d, J= 3.0 Hz, 1H), 7.70 (s, 1H), 7.48-7.45 (m, 1H), 6.76 (d, J = 7.6 Hz,1H), 5.48-5.23 (m, 1H), 4.89-4.70 (m, 2H), 3.84-3.30 (m, 4H), 2.24-1.91(m, 2H). Calculated (M + H): 444.08; Found (M + 1): 444.1. HPLC purity97.24% 450

3-(3,4- dichlorophenyl)-6-(2- (3-fluoropyrrolidin-1- yl)-2-oxoethyl)imidazo[1,2- c]pyrimidin-5(6H)- one ¹H NMR (400 MHz, DMSO- d₆)δ (ppm); 7.72 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.44-7.40(m, 2H), 6.70 (d, J = 7.6 Hz, 1H), 5.48-5.23 (m, 1H), 4.86-4.67 (m, 2H),3.86-3.36 (m, 4H), 2.24-2.06 (m, 2H). Calculated (M + H): 409.06; Found(M + H): 409.2. HPLC purity 99.37% 451

3-(3-chloro-4- fluorophenyl)-6-(2-(3- fluoropyrrolidin-1-yl)- 2-oxoethyl)imidazo[1,2- c]pyrimidin-5(6H)- one ¹H NMR (400 MHz, DMSO- d₆)δ (ppm); 7.67 (d, J = 6.8 Hz, 1H), 7.45-7.38 (m, 4H), 6.69 (d, J = 7.6Hz, 1H), 5.48- 5.23 (m, 1H), 4.86-4.67 (m, 2H), 3.85-3.27 (m, 4H), 2.24-2.06 (m, 2H). Calculated (M + H): 393.09; Found (M + 1): 393.2.2. HPLCpurity 99.94%

Example 452: Preparation of3-(3-chloro-4-fluorophenyl)-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-8methylimidazo[1,2-c]pyrimidin-5(6H)-one

Step 1:

Preparation of 5-bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine

To a solution of 5-bromo-2,4-dichloropyrimidine (5.0 g, 21.94 mmol) inethanol (100 mL) were added triethylamine (3.7 mL, 26.33 mmol) and2,2-dimethoxyethanamine (2.53 mL, 24.14 mmol) at room temperature andthe reaction mixture was stirred for 24 h. After completion of reaction,the reaction mixture was concentrated under reduced pressure. Theresidue was diluted with ethyl acetate (100 mL), washed with water (50mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to obtain crude product, which was purified bysilica gel column chromatography using 20% ethyl acetate in hexane aseluent to obtain title compound5-bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine (5.4 g, 83%yield) as white solid. Calculated (M+H): 295.97; Found (M+H): 296.0.

Step 2:

Preparation of 8-bromoimidazo[1,2-c]pyrimidin-5(6H)-one

To concentrated sulfuric acid (2 mL),5-bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine (1.0 g, 3.37mmol) was added at 0° C. and the resulting mixture was heated at 70° C.for 3 h. The reaction mixture was allowed to cool to room temperature,poured on to ice water and the pH was adjusted 6 to 7 using 2N sodiumhydroxide solution. The precipitated product was filtered, washed withcold water and dried to obtain the title compound8-bromoimidazo[1,2-c]pyrimidin-5(6H)-one (0.25 g, 34% yield) as a yellowsolid. Calculated (M+H): 213.95; Found (M+1): 214.0.

Step 3:

Preparation of8-bromo-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,2-c]pyrimidin-5(6H)-one

To a mixture of 8-bromoimidazo[1,2-c]pyrimidin-5(6H)-one (2.0 g, 9.344mmol) and potassium carbonate (3.87 g, 28.03 mmol) in dry N, N dimethylformamide, was added 2-chloro-1-(3-fluoropyrrolidin-1-yl)ethanone (1.85g, 11.21 mmol). The resulting mixture was heated at 75° C. for 3 h. Thereaction mixture was allowed to cool to room temperature, diluted withcold water (75 mL) and extracted with ethyl acetate (3×250 mL). Thecombined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated under vacuum to afford crude product, whichwas purified by silica gel (60-120) column chromatography using 3%methanol in dichloromethane to afford the title compound8-bromo-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazol[1,2-c]pyrimidin-5(6H)-one(1.0 g, 46% yield) as off white solid. Calculated (M+H): 343.01; Found(M+H): 343.0.

Step 4:

Preparation of ethyl6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-8-methylimidazo[1,2-c]pyrimidin-5(6H)-one

To a solution of8-bromo-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazo[1,2-c]pyrimidin-5(6H)-one(0.87 g, 2.54 mmol)) in 1,4-dioxane (10 mL) was added2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.07 mL, 7.61 mmol). Thereaction mixture was purged with argon for 10 minutes. Thentetrakis(triphenylphosphine)palladium [Pd(pph₃)₄] (0.3 g, 0.25 mmol) andpotassium carbonate (1.75 g, 12.77 mmol) were added under argonatmosphere and the reaction mixture was heated at 100° C. for 16 h.After completion of the reaction (monitored by TLC), the reactionmixture was allowed to cool to room temperature, filtered through celitepad and washed with ethyl acetate. The filtrate was concentrated toafford the crude product, which was purified by silica gel columnchromatography using 4% methanol in dichloromethane to afford the titlecompound ethyl6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-8-methylimidazo[1,2-c]pyrimidin-5(6H)-one(0.36 g, 51% yield) as off white solid. Calculated (M+H): 279.12; Found(M+H): 279.2.

Step 5:

Preparation of6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-3-iodo-8-methylimidazo[1,2-c]pyrimidin-5(6H)-one

To a mixture of ethyl6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-8-methylimidazo[1,2-c]pyrimidin-5(6H)-one(0.36 g, 1.29 mmol) and sodium acetate (0.53 g, 6.47 mmol) in methanol(20 mL) was added iodine (1.6 g, 6.47 mmol) at 0° C. The reactionmixture was allowed to warm to room temperature and stirred for 24 h.The reaction mixture was concentrated under vacuum, the residue wasdiluted 5M sodium thiosulphate solution (100 mL) and extracted withethyl acetate (3×250 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered, concentrated under vacuum to affordthe crude product, which was purified by silica gel columnchromatography using 4% methanol in dichloromethane to afford the titlecompound6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-3-iodo-8-methylimidazo[1,2-c]pyrimidin-5(6H)-one(0.26 g, 50% yield) as white solid. Calculated (M+H): 405.01; Found(M+1): 405.0.

Step 6:

Preparation of3-(3-chloro-4-fluorophenyl)-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-8-methylimidazo[1,2-c]pyrimidin-5(6H)-one

To a solution of6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-3-iodo-8-methylimidazo[1,2-c]pyrimidin-5(6H)-one(0.18 g, 0.45 mmol) and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid(0.08 g, 0.45 mmol) in 1,4-dioxane:water mixture (20 mL, 1:1), potassiumcarbonate (0.18 g, 1.33 mmol) was added. The reaction mixture was purgedwith argon for 10 min. Then1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex [Pd(dppf)Cl₂.DCM] (0.04 g, 0.05 mmol) was addedthe reaction mixture was heated at 100° C. for 4 h. The reaction mixturewas allowed to cool to room temperature, filtered through celite andwashed with ethyl acetate. The filtrate was washed with water (20 mL),brine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated to afford the crude compound, which was purified by silicagel column chromatography using 4% methanol in dichloromethane as eluentto afford the title compound3-(3-chloro-4-fluorophenyl)-6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-8-methylimidazo[1,2-c]pyrimidin-5(6H)-one(0.072 g, 40% yield) as pale brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.66 (d, J=5.6 Hz, 1H), 7.46-7.38 (m, 3H), 7.24 (s, 1H),5.48-5.23 (m, 1H), 4.82-4.62 (m, 2H), 3.85-3.38 (m, 4H), 2.30-1.96 (m,5H). Calculated (M+H): 407.1; Found (M+H): 407.1. HPLC purity: 99.57%.

TABLE 48 The following compounds were prepared by the method describedabove: Ex. No. Structure IUPAC Name Analytical data 453

3-(3,4-dichlorophenyl)- 6-(2-(3-fluoropyrrolidin- 1-yl)-2-oxoethyl)-8-methylimidazo[1,2- c]pyrimidin-5(6H)-one ¹H NMR (400 MHz, DMSO- d₆) δ(ppm); 7.71(s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J =7.2 Hz, 1H), 7.26 (s, 1H), 5.48-5.23 (m, 1H), 4.82-4.63 (m, 2H),3.85-3.45 (m, 4H), 2.23-1.94 (m, 5H). Calculated (M + H): 423.07; Found(M + 1): 423.1. HPLC purity 95.82% 454

3-(4-fluoro-3- (trifluoromethyl)phenyl)- 6-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-8- methylimidazo[1,2- c]pyrimidin-5(6H)-one ¹H NMR(400 MHz, DMSO- d₆) δ (ppm); 7.85-7.80 (m, 2H), 7.54-7.49 (m, 2H), 7.25(s, 1H), 5.48-5.23 (m, 1H), 4.82-4.67 (m, 2H), 3.76-3.54 (m, 4H),2.30-2.07 (m, 5H). Calculated (M + H): 441.13; Found (M + 1): 441.1.HPLC purity 99.03%

R. Biological Example

HEK293 cells with constructs conferring stable expression of the GRIN1gene and tetracycline-inducible expression of the GRIN2B gene (Chantest,Cleveland, Ohio) are grown to ˜75% confluence in tissue culture flasksat 37° C., 5% CO₂. NR2B expression is induced by overnight incubationwith 0.3-0.4 μg/ml tetracycline in the presence of 2.5 mM ARL-15896 at37° C., followed by moving to 30° C. for 3-5 hours. Cells are nextharvested using TripleExpress™ (Life Technologies, Carlsbad, Calif.)according to the manufacturer's instructions, first removing culturemedium, rinsing with Dulbecco's phosphate buffered saline (Ca²⁺ andMg²⁺-free), and then adding the TripleExpress™ reagent. Harvested cellsare spun down, washed twice in Ca²⁺— and Mg²⁺-free Hank's Balanced SaltSolution with 20 mM HEPES and 10 mM glucose, pH 7.4 (HHnoCa solution),and counted with viability assessed using Trypan Blue. Cells are loadedwith fluo-8 Ca²⁺-sensitive dye in HHnoCa solution according to themanufacturer's directions (AAT Bioquest, Sunnyvale, Calif.), incubatingat 37° C. for 20 minutes followed by 25 minutes at 22-25° C. After awash in HHnoCa to remove extracellular dye, cells are resuspended inHHnoCa and plated at 2×10⁷-3×10⁷ cells per well in a volume of 25μl/well in 384 well black-wall, clear bottom plates (Hamamatsu,Middlesex, N.J.). Plates are then centrifuged to create a monolayer inthe wells and stored in the dark until used.

Prior to analysis, compound plates are prepared with each compound at 6×the final desired concentration. From stock solutions at 10 mM in 100%DMSO, compounds are spotted in the desired amounts using an ECHO liquidhandler (Labcyte, Sunnyvale, Calif.) into wells of a 384-well plate andthen diluted with 50 μl of HHnoCa containing 750 nM Ro 25-6981 and 120μM 5,7-dichlorokynurenic acid (both purchased from Tocris Bioscience(Bristol, England) and maintained as 10 mM stock solutions in 100%DMSO). To insure complete compound dissolution, these plates are thenplaced in an orbital shaker for at least one hour. Also prepared priorto the assay is a co-agonist plate containing HHnoCa with 240 μMglutamate, 2.4 mM glycine, and 7.2 mM CaCl₂, which is 2.4× the desiredfinal concentration of each reagent. Both the compound plate andco-agonist plate are 384-well polypropylene plates from Thermo FisherScientific, Waltham, Mass.

The assay is performed by first adding 10 μl solution from each well ofthe compound plate described above to the cell plate using a CyBiWellliquid handler (Analytik Jena AG, Jena, Germany), followed by 10 minutespre-incubation in the dark. Cell plates are then loaded onto a HamamatsuFDSS 6000 plate reader. After a 30-second baseline, 25 μl is added toeach well from the co-agonist plate, and the fluorescence signal isrecorded for another 2 minutes. FDSS software applies shading andautofluorescence correction, and resultant raw fluorescence measurementsare exported in the form of a fluorescence ratio for each well to itsown reading at time zero in the experiment. In each plate, negativecontrol wells consist of wells where Ro 25-6981 and 5,7dichlorokynurenic acid are present and co-agonist is applied in theabsence of any added assay compound. Under these conditions, the Ca²⁺response to co-agonist is suppressed. Positive control wells alsopresent in each plate contain 5,7 dichlorokynurenic acid but no Ro25-6981, so that co-agonist addition results in a large Ca²⁺ response.Compounds tested are evaluated on the basis of their ability to reversethe suppression of the Ca²⁺ response mediated by Ro 25-6981, which isquantified as % reversal=100*(R−R_(neg))/(R_(pos)−R_(neg)) where R isthe fluorescence ratio for the test compound at the end of theexperiment and R_(neg) and R_(pos) are the end ratios for the negativeand positive controls, respectively. Using this equation, a compoundwould return 0% if it had no effect on the Ro 25-6981-mediatedsuppression of Ca²⁺ flux, whereas a compound that entirely reversed theeffect of Ro 25-6981 (to the level of co-agonist stimulation) wouldreturn 100%.

The results of the above assay are shown in Table 49.

TABLE 49 Ex. Response No. IUPAC Name Recovered (%) 3455-(4-chlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H- 18thieno[3,4-d]pyrimidin-4-one 3462-[5-(4-chlorophenyl)-4-oxo-3H,4H-thieno[3,4-d]pyrimidin-3-yl]-N- 0cyclopropylacetamide 3472-[5-(4-chlorophenyl)-4-oxo-3H,4H-thieno[3,4-d]pyrimidin-3-yl]-N- 2cyclobutylacetamide 3485-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]- 263H,4H-thieno[3,4-d]pyrimidin-4-one 3493-[2-(azetidin-1-yl)-2-oxoethyl]-5-(4-chlorophenyl)-3H,4H-thieno[3,4- 3d]pyrimidin-4-one 3703-[2-(azetidin-1-yl)-2-oxoethyl]-5-(4-chlorophenyl)-3H,4H,5H- 4pyrrolo[3,2-d]pyrimidin-4-one 3715-(4-chlorophenyl)-3-[2-(morpholin-4-yl)-2-oxoethyl]-3H,4H,5H- 1pyrrolo[3,2-d]pyrimidin-4-one 3725-(4-chlorophenyl)-3-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]- 13H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one 3735-(4-chlorophenyl)-3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]- 33H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one 3505-(4-chlorophenyl)-3-[2-oxo-2-(piperidin-1-yl)ethyl]-3H,4H- 0thieno[3,4-d]pyrimidin-4-one 3515-(4-chlorophenyl)-3-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]-3H,4H- 1thieno[3,4-d]pyrimidin-4-one 3525-(4-chlorophenyl)-3-[2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl]- 73H,4H-thieno[3,4-d]pyrimidin-4-one 3535-(4-chlorophenyl)-3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]- 13H,4H-thieno[3,4-d]pyrimidin-4-one 3745-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]- 43H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one 3752-[5-(4-chlorophenyl)-4-oxo-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-3-yl]- 0N-cyclopropylacetamide 3765-(4-chlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H,5H- 3pyrrolo[3,2-d]pyrimidin-4-one 3545-(4-chlorophenyl)-3-[2-(morpholin-4-yl)-2-oxoethyl]-3H,4H- 1thieno[3,4-d]pyrimidin-4-one 3775-(4-chlorophenyl)-3-[2-oxo-2-(piperidin-1-yl)ethyl]-3H,4H,5H- 1pyrrolo[3,2-d]pyrimidin-4-one 3782-[5-(4-chlorophenyl)-4-oxo-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-3-yl]- 1N-cyclobutylacetamide 3795-(4-chlorophenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1- 5yl]ethyl}-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one 3555-(4-chlorophenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1- 10yl]ethyl}-3H,4H-thieno[3,4-d]pyrimidin-4-one 2955-(4-chlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3,4- 1dihydroquinazolin-4-one 2965-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-3,4- 9dihydroquinazolin-4-one 2975-(4-chlorophenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1- 3yl]ethyl}-3,4-dihydroquinazolin-4-one 2985-(4-chlorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3,4- 9dihydroquinazolin-4-one 3563-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]- 113H,4H-thieno[3,4-d]pyrimidin-4-one 3885-(4-chlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-furo[2,3- 8d]pyrimidin-4-one 3895-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]- 83H,4H-furo[2,3-d]pyrimidin-4-one 3875-(4-chlorophenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1- 7yl]ethyl}-3H,4H-furo[2,3-d]pyrimidin-4-one 3573-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-5-[4- 2(trifluoromethyl)phenyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 3583-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-[4- 12(trifluoromethyl)phenyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 3833-(4-chlorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H- 1[1,2]oxazolo[5,4-d]pyrimidin-4-one 3843-(4-chlorophenyl)-5-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1- 2yl]ethyl}-4H,5H-[1,2]oxazolo[5,4-d]pyrimidin-4-one 3853-(4-chlorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]- 44H,5H-[1,2]oxazolo[5,4-d]pyrimidin-4-one 3863-(4-chlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H- 4[1,2]oxazolo[5,4-d]pyrimidin-4-one 3803-(4-chlorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H- 6[1,2]thiazolo[5,4-d]pyrimidin-4-one 1505-(4-chlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H,7H- 31pyrrolo[2,3-d]pyrimidin-4-one 1515-(4-chlorophenyl)-7-methyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]- 173H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1525-(4-chlorophenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1- 10yl]ethyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1535-(4-chlorophenyl)-7-methyl-3-{2-oxo-2-[2- 35(trifluoromethyl)pyrrolidin-1-yl]ethyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1545-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]- 363H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3813-(4-chlorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]- 24H,5H-[1,2]thiazolo[5,4-d]pyrimidin-4-one 3823-(4-chlorophenyl)-5-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1- 9yl]ethyl}-4H,5H-[1,2]thiazolo[5,4-d]pyrimidin-4-one 1555-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-7- 24methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3595-(3-chloro-4-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H- 35thieno[3,4-d]pyrimidin-4-one 3605-(3-chloro-4-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 39oxoethyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 3665-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1- 34yl)ethyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 1565-(3-chloro-4-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]- 363H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1485-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1- 66yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1575-[4-chloro-3-(trifluoromethyl)phenyl]-7-ethyl-3-[2-oxo-2-(pyrrolidin-70 1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1585-[4-chloro-3-(trifluoromethyl)phenyl]-7-methyl-3-[2-oxo-2- 72(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3625-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3,3-difluoroazetidin-1- 39yl)-2-oxoethyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 3353-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 23yl)ethyl]-4H,5H-thieno[2,3-d]pyridazin-4-one 1595-(3-chloro-4-fluorophenyl)-7-methyl-3-[2-oxo-2-(pyrrolidin-1- 25yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1605-(3-chloro-4-fluorophenyl)-7-ethyl-3-[2-oxo-2-(pyrrolidin-1- 42yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1615-(3-chloro-4-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 58oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1625-(3-chloro-4-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 40oxoethyl]-7-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1635-(3-chloro-4-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 48oxoethyl]-7-ethyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1645-(4-chloro-3-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]- 483H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1655-(4-chloro-3-fluorophenyl)-7-methyl-3-[2-oxo-2-(pyrrolidin-1- 25yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1665-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3,3-difluoroazetidin-1- 65yl)-2-oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3315-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1- 8yl)ethyl]-3H,4H-thieno[2,3-d][1,2,3]triazin-4-one 3363-(4-chloro-3-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H- 3thieno[2,3-d]pyridazin-4-one 3373-(3-chloro-4-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H- 7thieno[2,3-d]pyridazin-4-one 3383-(3,4-dichlorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H- 15thieno[2,3-d]pyridazin-4-one 13-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 83yl)ethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 53-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3,3-difluoroazetidin-1- 139yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 43-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-107 2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 23-(4-chloro-3-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H- 34thieno[3,2-c]pyridin-4-one 63-(4-chloro-3-fluorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2- 41oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 73-(4-chloro-3-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 49oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 3335-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3,3-difluoroazetidin-1- 13yl)-2-oxoethyl]-3H,4H-thieno[2,3-d][1,2,3]triazin-4-one 3325-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-20 2-oxoethyl]-3H,4H-thieno[2,3-d][1,2,3]triazin-4-one 3345-[4-chloro-3-(trifluoromethyl)phenyl]-3-{2-oxo-2-[2- 2(trifluoromethyl)pyrrolidin-1-yl]ethyl}-3H,4H-thieno[2,3-d][1,2,3]triazin-4-one 1675-(4-chloro-3-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 35oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1685-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3,3-difluoroazetidin-1- 55yl)-2-oxoethyl]-7-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1695-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3,3-difluoroazetidin-1- 57yl)-2-oxoethyl]-7-ethyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1705-(4-chloro-3-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 18oxoethyl]-7-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1715-(4-chloro-3-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 15oxoethyl]-7-ethyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 33-(3-chloro-4-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H- 60thieno[3,2-c]pyridin-4-one 3393-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3,3-difluoroazetidin-1- 20yl)-2-oxoethyl]-4H,5H-thieno[2,3-d]pyridazin-4-one 3403-(4-chloro-3-fluorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2- 3oxoethyl]-4H,5H-thieno[2,3-d]pyridazin-4-one 3413-(3-chloro-4-fluorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2- 8oxoethyl]-4H,5H-thieno[2,3-d]pyridazin-4-one 3423-(4-chloro-3-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 4oxoethyl]-4H,5H-thieno[2,3-d]pyridazin-4-one 3433-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 15oxoethyl]-4H,5H-thieno[2,3-d]pyridazin-4-one 83-(3-chloro-4-fluorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2- 66oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 93-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 81oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1725-(3-chloro-4-fluorophenyl)-7-(2-fluoroethyl)-3-[2-oxo-2-(pyrrolidin- 401-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3443-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-−1 2-oxoethyl]-4H,5H-thieno[2,3-d]pyridazin-4-one 3635-(4-chloro-3-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 16oxoethyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 1735-(4-chloro-3-fluorophenyl)-7-(2-fluoroethyl)-3-[2-oxo-2-(pyrrolidin- 321-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3675-(4-chloro-3-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H- 15thieno[3,4-d]pyrimidin-4-one 3645-(4-chloro-3-fluorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2- 35oxoethyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 1495-[4-chloro-3-(trifluoromethyl)phenyl]-7-(2-fluoroethyl)-3-[2-oxo-2- 64(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3305-(3-chloro-4-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H- 6thieno[2,3-d][1,2,3]triazin-4-one 3687-bromo-5-(4-chloro-3-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1- 41yl)ethyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 3695-(4-chloro-3-fluorophenyl)-7-methyl-3-[2-oxo-2-(pyrrolidin-1- 33yl)ethyl]-3H,4H-thieno[3,4-d]pyrimidin-4-one 3173-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 8yl)ethyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one 3655-(4-chloro-3-fluorophenyl)-3-{2-oxo-2-[2- 4(trifluoromethyl)pyrrolidin-1-yl]ethyl}-3H,4H-thieno[3,4-d]pyrimidin-4-one 103-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]- 1024H,5H-thieno[3,2-c]pyridin-4-one 113-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-99 2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1855-[4-chloro-3-(trifluoromethyl)phenyl]-7-(2-methoxyethyl)-3-[2-oxo- 762-(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1865-(3-chloro-4-fluorophenyl)-7-(2-methoxyethyl)-3-[2-oxo-2- 18(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1905-[4-chloro-3-(trifluoromethyl)phenyl]-7-cyclopropyl-3-[2-oxo-2- 71(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1875-(4-chloro-3-fluorophenyl)-7-(2-methoxyethyl)-3-[2-oxo-2- 9(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 243-[4-chloro-3-(trifluoromethyl)phenyl]-5-[3-(3-fluoropyrrolidin-1-yl)- 33-oxopropyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1745-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-91 2-oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1755-(3,4-dichlorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]- 773H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1765-[3-chloro-4-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-63 2-oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3193-(4-chloro-3-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]- 41H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one 1775-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-85 2-oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1785-(3-chloro-4-fluorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2- 54oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1975-(4-chloro-3-fluorophenyl)-7-(2-hydroxyethyl)-3-[2-oxo-2- 7(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1915-(4-chloro-3-fluorophenyl)-7-cyclopropyl-3-[2-oxo-2-(pyrrolidin-1- 36yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1795-(4-chloro-3-fluorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2- 37oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1945-[4-chloro-3-(trifluoromethyl)phenyl]-7-(2-hydroxyethyl)-3-[2-oxo-2- 2(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1925-(3-chloro-4-fluorophenyl)-7-cyclopropyl-3-[2-oxo-2-(pyrrolidin-1- 42yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 3203-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3,3-difluoroazetidin-1- 9yl)-2-oxoethyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one 3183-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-26 2-oxoethyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one 1955-(3-chloro-4-fluorophenyl)-7-(2-hydroxyethyl)-3-[2-oxo-2- 21(pyrrolidin-1-yl)ethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 123-(5,6-dichloropyridin-3-yl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 35oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1805-(5,6-dichloropyridin-3-yl)-3-[2-(3-fluoropyrrolidin-1-yl)-2- 15oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 2998-[4-chloro-3-(trifluoromethyl)phenyl]-2-[2-(3-fluoropyrrolidin-1-yl)-32 2-oxoethyl]-1,2-dihydroisoquinolin-1-one 3008-[4-chloro-3-(trifluoromethyl)phenyl]-2-[2-oxo-2-(pyrrolidin-1- 37yl)ethyl]-1,2-dihydroisoquinolin-1-one 3018-[4-chloro-3-(trifluoromethyl)phenyl]-2-[2-(3,3-difluoroazetidin-1- 28yl)-2-oxoethyl]-1,2-dihydroisoquinolin-1-one 133-[3-chloro-4-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-90 2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1983-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 104yl)ethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1993-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-47 2-oxoethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2003-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3,3-difluoroazetidin-1- 18yl)-2-oxoethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2013-(4-chloro-3-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1-{[2- 62(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2023-(4-chloro-3-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 32oxoethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2123-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3,3-difluoroazetidin-1- 107yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1815-[4-chloro-3-(trifluoromethyl)phenyl]-3-{2-[(3R,4S)-3,4- 69difluoropyrrolidin-1-yl]-2-oxoethyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 2033-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-42 2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2043-(4-chloro-3-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 47oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2113-(4-chloro-3-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]- 551H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2133-(4-chloro-3-fluorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2- 109oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 143-[4-chloro-3-(trifluoromethyl)phenyl]-5-{2-[(3R,4S)-3,4- 99difluoropyrrolidin-1-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4- one15 3-[4-chloro-3-(trifluoromethyl)phenyl]-5-{2-[(3S)-3-fluoropyrrolidin-95 1-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 163-(3,4-dichlorophenyl)-5-{2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-2- 107oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 253-[6-chloro-5-(trifluoromethyl)pyridin-3-yl]-5-[2-(3-fluoropyrrolidin-28 1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 3028-(3-chloro-4-fluorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2- 40oxoethyl]-1,2-dihydroisoquinolin-1-one 3038-(3-chloro-4-fluorophenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,2- 46dihydroisoquinolin-1-one 3048-(3,4-dichlorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-1,2-60 dihydroisoquinolin-1-one 2053-(3-chloro-4-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1-{[2- 59(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2063-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 107oxoethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 173-[4-chloro-3-(trifluoromethyl)phenyl]-5-{2-[(3R)-3-fluoropyrrolidin- 991-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 263-[4-fluoro-3-(trifluoromethyl)phenyl]-5-{2-[(3S)-3-fluoropyrrolidin-103 1-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 273-[4-fluoro-3-(trifluoromethyl)phenyl]-5-{2-[(3R)-3-fluoropyrrolidin- 811-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 285-{2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-2-oxoethyl}-3-[4-fluoro-3- 94(trifluoromethyl)phenyl]-4H,5H-thieno[3,2-c]pyridin-4-one 3078-(4-chloro-3-fluorophenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,2- 24dihydroisoquinolin-1-one 3068-(4-chloro-3-fluorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2- 25oxoethyl]-1,2-dihydroisoquinolin-1-one 3058-(4-chloro-3-fluorophenyl)-2-[2-(3,3-difluoroazetidin-1-yl)-2- 23oxoethyl]-1,2-dihydroisoquinolin-1-one 3088-(3,4-dichlorophenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,2- 78dihydroisoquinolin-1-one 3098-(3-chloro-4-fluorophenyl)-2-[2-(3,3-difluoroazetidin-1-yl)-2- 41oxoethyl]-1,2-dihydroisoquinolin-1-one 293-(3,4-dichlorophenyl)-5-{2-[(3R)-3-fluoropyrrolidin-1-yl]-2- 104oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 303-(3,4-dichlorophenyl)-5-{2-[(3S)-3-fluoropyrrolidin-1-yl]-2- 96oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 313-(5-chlorothiophen-2-yl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]- 344H,5H-thieno[3,2-c]pyridin-4-one 1825-[6-chloro-5-(trifluoromethyl)pyridin-3-yl]-3-[2-(3,3- 18difluoroazetidin-1-yl)-2-oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 2073-(3-chloro-4-fluorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2- 69oxoethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2083-(3-chloro-4-fluorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]- 601H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2093-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 53oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2143-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]- 841H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2153-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-89 2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2165-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-3-[4-fluoro-3- 101(trifluoromethyl)phenyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 987-bromo-3-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2- 40(pyrrolidin-1-yl)ethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2552-[3-(3-chloro-4-fluorophenyl)-4-oxo-1H,4H,5H-pyrrolo[3,2- −1c]pyridin-5-yl]acetamide 2173-(3,4-dichlorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1H,4H,5H- 70pyrrolo[3,2-c]pyridin-4-one 993-[4-chloro-3-(trifluoromethyl)phenyl]-4-oxo-5-[2-oxo-2-(pyrrolidin- 371-yl)ethyl]-4H,5H-thieno[3,2-c]pyridine-7-carbonitrile 1013-[4-chloro-3-(trifluoromethyl)phenyl]-7-cyclopropyl-5-[2-oxo-2- 29(pyrrolidin-1-yl)ethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1835-[6-chloro-5-(trifluoromethyl)pyridin-3-yl]-3-[2-(3-fluoropyrrolidin-14 1-yl)-2-oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 2183-(3-chloro-4-fluorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2- 71oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1885-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-53 2-oxoethyl]-7-(2-methoxyethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 219 3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1-91 yl)ethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 3107-[4-chloro-3-(trifluoromethyl)phenyl]-2-[2-oxo-2-(pyrrolidin-1- 3yl)ethyl]-1,2-dihydroisoquinolin-1-one 3117-[4-chloro-3-(trifluoromethyl)phenyl]-2-[2-(3-fluoropyrrolidin-1-yl)- 62-oxoethyl]-1,2-dihydroisoquinolin-1-one 3127-[4-chloro-3-(trifluoromethyl)phenyl]-2-[2-(3,3-difluoroazetidin-1- 3yl)-2-oxoethyl]-1,2-dihyroisoquinolin-1-one 3137-cyclopropyl-5-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(3- 88fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 184 7-ethyl-5-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(3- 66fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 1965-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-34 2-oxoethyl]-7-(2-hydroxyethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one 106 3-[4-chloro-3-(trifluoromethyl)phenyl]-7-methyl-5-[2-oxo-2- 76(pyrrolidin-1-yl)ethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1023-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 23yl)ethyl]-7-phenyl-4H,5H-thieno[3,2-c]pyridin-4-one 323-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoroazetidin-1-yl)-2-60 oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 3273-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]- 544H,5H-pyrazolo[1,5-a]pyrazin-4-one 3263-(3,4-dichlorophenyl)-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H- 29pyrazolo[1,5-a]pyrazin-4-one 3137-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[2-oxo-2-(pyrrolidin-1- 5yl)ethyl]-1,2-dihydroisoquinolin-1-one 3147-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[2-(3-fluoropyrrolidin-1-yl)- 82-oxoethyl]-1,2-dihydroisoquinolin-1-one 3157-(3,4-dichlorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-1,2- 2dihydroisoquinolin-1-one 2383-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-65 2-oxoethyl]-1-(methoxymethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one103 3-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 32yl)ethyl]-7-(pyridin-4-yl)-4H,5H-thieno[3,2-c]pyridin-4-one 1895-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-39 2-oxoethyl]-7-(methoxymethyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4- one239 1-ethyl-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3- 86fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one325 3-(3,4-dichlorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-50 4H,5H-pyrazolo[1,5-a]pyrazin-4-one 3213-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-46 2-oxoethyl]-4H,5H-pyrazolo[1,5-a]pyrazin-4-one 3245-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-3-[4-fluoro-3- 51(trifluoromethyl)phenyl]-4H,5H-pyrazolo[1,5-a]pyrazin-4-one 3233-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 40yl)ethyl]-4H,5H-pyrazolo[1,5-a]pyrazin-4-one 3223-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoroazetidin-1-yl)-2-33 oxoethyl]-4H,5H-pyrazolo[1,5-a]pyrazin-4-one 1003-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-5-[2-oxo-2-(pyrrolidin- 341-yl)ethyl]-4H,5H-thieno[3,2-c]pyridine-7-carbonitrile 1083-[4-fluoro-3-(trifluoromethyl)phenyl]-N-hydroxy-4-oxo-5-[2-oxo-2- 64(pyrrolidin-1-yl)ethyl]-4H,5H-thieno[3,2-c]pyridine-7- carboximidamide2303-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-109 2-oxoethyl]-1-phenyl-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2253-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-83 2-oxoethyl]-1-(pyridin-2-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 3167-(3,4-dichlorophenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,2- 2dihydroisoquinolin-1-one 333-(3,4-dichlorophenyl)-5-[2-(3-fluoroazetidin-1-yl)-2-oxoethyl]- 544H,5H-thieno[3,2-c]pyridin-4-one 343-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoroazetidin-1-yl)-2-79 oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1073-[4-fluoro-3-(trifluoromethyl)phenyl]-7-methyl-5-[2-oxo-2- 63(pyrrolidin-1-yl)ethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1043-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 22yl)ethyl]-7-phenyl-4H,5H-thieno[3,2-c]pyridin-4-one 1053-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 22yl)ethyl]-7-(pyridin-4-yl)-4H,5H-thieno[3,2-c]pyridin-4-one 1113-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-97 2-oxoethyl]-7-(hydroxymethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 353-(5,6-dichloropyridin-3-yl)-5-[2-(3,4-difluoropyrrolidin-1-yl)-2- 28oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 363-[6-chloro-5-(trifluoromethyl)pyridin-3-yl]-5-[2-(3,4- 54difluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one1093-[4-fluoro-3-(trifluoromethyl)phenyl]-7-(1,2,4-oxadiazol-3-yl)-5-[2- 14oxo-2-(pyrrolidin-1-yl)ethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2563-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-54 2-oxoethyl]-1-(2-hydroxyethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one2243-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-109 2-oxoethyl]-1-(pyridin-2-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one1123-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-89 2-oxoethyl]-7-(pyrrolidin-1-ylmethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 2263-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-69 2-oxoethyl]-1-(pyridin-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1133-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-5-[2-oxo-2-(pyrrolidin- 471-yl)ethyl]-4H,5H-thieno[3,2-c]pyridine-7-carboximidamide 4483-[4-fluoro-3-(trifluoromethyl)phenyl]-6-[2-(3-fluoropyrrolidin-1-yl)-14 2-oxoethyl]-5H,6H-imidazo[1,2-c]pyrimidin-5-one 4493-[6-chloro-5-(trifluoromethyl)pyridin-3-yl]-6-[2-(3-fluoropyrrolidin-5.2 1-yl)-2-oxoethyl]-5H,6H-imidazo[1,2-c]pyrimidin-5-one 2401-[2-(dimethylamino)ethyl]-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5- 29[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2573-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-20 2-oxoethyl]-1-(2-hydroxy-2-methylpropyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2411-(ethoxymethyl)-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3- 61fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one1103-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-33 2-oxoethyl]-N-hydroxy-4-oxo-4H,5H-thieno[3,2-c]pyridine-7-carboximidamide 3918-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[2-oxo-2-(pyrrolidin-1- 77yl)ethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 3908-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[2-(3-fluoropyrrolidin-1-yl)-51 2-oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 2311-cyclopropyl-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3- 90fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one37 3-(5-chloro-6-fluoropyridin-3-yl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-22 oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2273-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-42 2-oxoethyl]-1-(pyridin-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1143-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-oxo-2-(pyrrolidin-1- 15yl)ethyl]-7-(pyrrolidin-1-yl)-4H,5H-thieno[3,2-c]pyridin-4-one 1187-(azetidin-1-ylmethyl)-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2- 77(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one220 5-[2-(3,4-difluoropyrrolidin-1-yl)-2-oxoethyl]-3-[4-fluoro-3- 120(trifluoromethyl)phenyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2585-[2-(3,4-difluoropyrrolidin-1-yl)-2-oxoethyl]-3-[4-fluoro-3- 13(trifluoromethyl)phenyl]-1-(2-hydroxy-2-methylpropyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2425-[2-(3,4-difluoropyrrolidin-1-yl)-2-oxoethyl]-3-[4-fluoro-3- 110(trifluoromethyl)phenyl]-1-(methoxymethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2213-[6-chloro-5-(trifluoromethyl)pyridin-3-yl]-5-[2-(3,4- 43difluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1177-[(diethylamino)methyl]-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2- 30(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one116 7-[(dimethylamino)methyl]-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-70 [2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1263-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-46 2-oxoethyl]-7-(methoxymethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 383-(5-chloro-6-fluoropyridin-3-yl)-5-[2-(3,4-difluoropyrrolidin-1-yl)-2-18 oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2283-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 39oxoethyl]-1-(pyridin-2-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1277-(ethoxymethyl)-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3- 48fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2103-(5,6-dichloropyridin-3-yl)-5-[2-(3,4-difluoropyrrolidin-1-yl)-2- 26oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1343-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-130 2-oxoethyl]-7-[(1E)-(hydroxyimino)methyl]-4H,5H-thieno[3,2-c]pyridin-4-one 4503-(3,4-dichlorophenyl)-6-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]- 335H,6H-imidazo[1,2-c]pyrimidin-5-one 4513-(3-chloro-4-fluorophenyl)-6-[2-(3-fluoropyrrolidin-1-yl)-2- 23oxoethyl]-5H,6H-imidazo[1,2-c]pyrimidin-5-one 1157-(azetidin-1-yl)-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3- 8.3fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2433-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-96 2-oxoethyl]-1-(pyrimidin-2-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one2443-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-110 2-oxoethyl]-1-(pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one128 3-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-y1)-2- 23oxoethyl]-7-(methoxymethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 1293-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 39oxoethyl]-7-(hydroxymethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 1303-(3-chloro-4-fluorophenyl)-7-(ethoxymethyl)-5-[2-(3- 42fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2603-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-68 2-oxoethyl]-1-(hydroxymethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one245 3-(3-chloro-4-fluorophenyl)-1-[2-(dimethylamino)ethyl]-5-[2-(3- 14fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one259 3-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 35oxoethyl]-1-(2-hydroxy-2-methylpropyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2463-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 34oxoethyl]-1-(methoxymethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2473-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 51oxoethyl]-1-methyl-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2293-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-1- 78(pyridin-2-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1353-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-11 2-oxoethyl]-7-[(1Z)-1-(hydroxyimino)ethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1313-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-7- 72(hydroxymethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 1323-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-7- 20(methoxymethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 1333-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-9.9 2-oxoethyl]-7-(2-hydroxypropan-2-yl)-4H,5H-thieno[3,2-c]pyridin-4-one 248 3-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 59oxoethyl]-1-(pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2323-(3-chloro-4-fluorophenyl)-1-cyclopropyl-5-[2-(3-fluoropyrrolidin-1- 66yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2613-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 29oxoethyl]-1-(oxetan-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2331-cyclopropyl-3-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-85 oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 3928-(3-chloro-4-fluorophenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1H,2H-118 pyrrolo[1,2-a]pyrazin-1-one 3938-(3-chloro-4-fluorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2- 49oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 1193-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 75oxoethyl]-7-(pyrrolidin-1-ylmethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 1203-(3-chloro-4-fluorophenyl)-7-[(dimethylamino)methyl]-5-[2-(3- 61fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 3948-(3,4-dichlorophenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1H,2H- 62pyrrolo[1,2-a]pyrazin-1-one 3958-(3,4-dichlorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]- 581H,2H-pyrrolo[1,2-a]pyrazin-1-one 1213-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-7- 59(pyrrolidin-1-ylmethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 1227-(azetidin-1-ylmethyl)-3-(3,4-dichlorophenyl)-5-[2-(3- 27fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1233-(3,4-dichlorophenyl)-7-[(dimethylamino)methyl]-5-[2-(3- 70fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2493-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-1- 70(methoxymethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 1247-(azetidin-1-ylmethyl)-3-(3-chloro-4-fluorophenyl)-5-[2-(3- 76fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2623-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-44 2-oxoethyl]-1-(pyridazin-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one250 3-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-1-62 methyl-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2633-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-72 2-oxoethyl]-1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2653-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-61 2-oxoethyl]-1-(oxetan-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2643-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 49oxoethyl]-1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2513-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-61 2-oxoethyl]-1-methyl-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2343-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-80 2-oxoethyl]-1-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2663-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-95 2-oxoethyl]-1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2723-(3,4-dichlorophenyl)-1-ethyl-5-[2-(3-fluoropyrrolidin-1-yl)-2- 33oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 393-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 140oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2523-[4-fluoro-3-(trifluoromethyl)phenyl]-1-(2-fluoroethyl)-5-[2-(3- 96fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one40 3-(3-chloro-4-fluorophenyl)-5-{2-[(3S)-3-fluoropyrrolidin-1-yl]-2- 46oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 413-(3-chloro-4-fluorophenyl)-5-{2-[(3R)-3-fluoropyrrolidin-1-yl]-2- 77oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 2533-(3-chloro-4-fluorophenyl)-1-(2-fluoroethyl)-5-[2-(3- 66fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one274 3-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 94oxoethyl]-1-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one4118-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[2-(3-fluoropyrrolidin-1-yl)-59 2-oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4533-(3,4-dichlorophenyl)-6-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-8- 26methyl-5H,6H-imidazo[1,2-c]pyrimidin-5-one 4523-(3-chloro-4-fluorophenyl)-6-[2-(3-fluoropyrrolidin-1-yl)-2- 7.5oxoethyl]-8-methyl-5H,6H-imidazo[1,2-c]pyrimidin-5-one 4543-[4-fluoro-3-(trifluoromethyl)phenyl]-6-[2-(3-fluoropyrrolidin-1-yl)-35 2-oxoethyl]-8-methyl-5H,6H-imidazo[1,2-c]pyrimidin-5-one 4271-[4-fluoro-3-(trifluoromethyl)phenyl]-7-[2-(3-fluoropyrrolidin-1-yl)-19 2-oxoethyl]-3-methyl-7H,8H-imidazo[1,5-a]pyrazin-8-one 4281-(3-chloro-4-fluorophenyl)-7-[2-(3-fluoropyrrolidin-1-yl)-2- 18oxoethyl]-3-methyl-7H,8H-imidazo[1,5-a]pyrazin-8-one 4291-(3,4-dichlorophenyl)-7-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3- 11methyl-7H,8H-imidazo[1,5-a]pyrazin-8-one 2753-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-1- 100(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2763-(3-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-5-[2-(3- 50fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one2773-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoropyrrolidin-1-yl)-78 2-oxoethyl]-1-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 235 3-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-40 oxoethyl]-1-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2791-(2,2-difluoroethyl)-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3- 71fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one4321-(3-chloro-4-fluorophenyl)-3-cyclopropyl-7-[2-(3-fluoropyrrolidin-1- 19yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 4138-(3,4-dichlorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-4- 43methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 423-(3,4-dichlorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 150oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 433-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoro-3- 160methylazetidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 4333-cyclopropyl-1-(3,4-dichlorophenyl)-7-[2-(3-fluoropyrrolidin-1-yl)-2-68 oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 4343-cyclopropyl-1-[4-fluoro-3-(trifluoromethyl)phenyl]-7-[2-(3- 40fluoropyrrolidin-1-yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8- one2763-(3,4-dichlorophenyl)-1-(2,2-difluoroethyl)-5-[2-(3-fluoropyrrolidin-78 1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 4148-(3-chloro-4-fluorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2- 112oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4126-bromo-8-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[2-(3- 38fluoropyrrolidin-1-yl)-2-oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4156-bromo-8-(3-chloro-4-fluorophenyl)-2-[2-(3-fluoropyrrolidin-1-yl)-2- 52oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4236-bromo-8-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[2-(3- 72fluoropyrrolidin-1-yl)-2-oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 3968-(3,4-dichlorophenyl)-2-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 140oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 443-(3-chloro-4-fluorophenyl)-5-[2-(3-cyclopropyl-3-fluoroazetidin-1- 63yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 455-[2-(3-cyclopropyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3-[4-fluoro-3- 12(trifluoromethyl)phenyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2833-(3,4-dichlorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-1- 82(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2223-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoro-3- 86methylazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 465-[2-(azetidin-1-yl)-2-oxoethyl]-3-(3-chloro-4-fluorophenyl)-4H,5H- 26thieno[3,2-c]pyridin-4-one 473-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoroazetidin-1-yl)-2-oxoethyl]- 234H,5H-thieno[3,2-c]pyridin-4-one 483-(3-chloro-4-fluorophenyl)-5-[2-(3-methylazetidin-1-yl)-2-oxoethyl]- 674H,5H-thieno[3,2-c]pyridin-4-one 1253-(3-chloro-4-fluorophenyl)-7-[(3-fluoroazetidin-1-yl)methyl]-5-[2-(3-53 fluoropyrrolidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one273 3-(3,4-dichlorophenyl)-1-(2-fluoroethyl)-5-[2-(3-fluoropyrrolidin-1-93 yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2673-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoropyrrolidin-1-yl)-2- 27oxoethyl]-1-(1-methyl-1H-1,2,3-triazol-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 3978-(3-chloro-4-fluorophenyl)-2-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 140oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 495-[2-(3-cyclopropyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(3,4- 26dichlorophenyl)-4H,5H-thieno[3,2-c]pyridin-4-one 503-(3,4-dichlorophenyl)-5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 96oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 515-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3-[4-fluoro-3- 57(trifluoromethyl)phenyl]-4H,5H-thieno[3,2-c]pyridin-4-one 523-(3-chloro-4-fluorophenyl)-5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 130oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 533-(3,4-dichlorophenyl)-5-[2-(3-fluoro-3-phenylazetidin-1-yl)-2- 24oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 543-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoro-3- 17phenylazetidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 553-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-hydroxy-3- 14methylazetidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2233-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 562-[3-(3-chloro-4-fluorophenyl)-4-oxo-4H,5H-thieno[3,2-c]pyridin-5- 7.3yl]-N-(2,2,2-trifluoroethyl)acetamide 3988-(3-chloro-4-fluorophenyl)-2-[2-(3-cyclopropyl-3-fluoroazetidin-1- 43yl)-2-oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 3998-(3-chloro-4-fluorophenyl)-2-[2-(3-fluoro-3-phenylazetidin-1-yl)-2- 1.5oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 2683-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoro-3- 52methylazetidin-1-yl)-2-oxoethyl]-1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 573-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-phenylazetidin-1-yl)-2- 15oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 583-(3-chloro-4-fluorophenyl)-5-[2-(3-hydroxy-3-methylazetidin-1-yl)- 102-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 593-(3,4-dichlorophenyl)-5-[2-(3-methylazetidin-1-yl)-2-oxoethyl]- 1104H,5H-thieno[3,2-c]pyridin-4-one 603-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-methylazetidin-1-yl)-2-76 oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 613-(3,4-dichlorophenyl)-5-[2-(3-hydroxy-3-methylazetidin-1-yl)-2- 16oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 623-(3-chloro-4-fluorophenyl)-5-[2-(3-methoxy-3-methylazetidin-1-yl)- 112-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 4008-(3-chloro-4-fluorophenyl)-2-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 97oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 633-(3,4-dichlorophenyl)-5-[2-(3-methoxy-3-methylazetidin-1-yl)-2- 16oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 643-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-methoxy-3- 22methylazetidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 653-(3-chloro-4-fluorophenyl)-5-(2-{6,6-difluoro-3- 13azabicyclo[3.1.0]hexan-3-yl}-2-oxoethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 663-(3,4-dichlorophenyl)-5-(2-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- 26yl}-2-oxoethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 673-(3-chloro-4-fluorophenyl)-5-(2-{2-oxa-6-azaspiro[3.3]heptan-6-yl}- 4.42-oxoethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 683-(3,4-dichlorophenyl)-5-(2-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-2- 13oxoethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 693-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(2-{2-oxa-6- 16azaspiro[3.3]heptan-6-yl}-2-oxoethyl)-4H,5H-thieno[3,2-c]pyridin-4- one269 3-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2-130 oxoethyl]-1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 932-[3-(3-chloro-4-fluorophenyl)-4-oxo-4H,5H-thieno[3,2-c]pyridin-5- 4.1yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide 705-[2-(3-cyclopropyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(5,6- 64dichloropyridin-3-yl)-4H,5H-thieno[3,2-c]pyridin-4-one 715-(2-{5-azaspiro[2.3]hexan-5-yl}-2-oxoethyl)-3-(3-chloro-4- 46fluorophenyl)-4H,5H-thieno[3,2-c]pyridin-4-one 725-(2-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2-oxoethyl)-3-[4- 37fluoro-3-(trifluoromethyl)phenyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2843-(3,4-dichlorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 5.2oxoethyl]-1-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 73 tert-butylN-(1-{2-[3-(3,4-dichlorophenyl)-4-oxo-4H,5H-thieno[3,2- 9.8c]pyridin-5-yl]acetyl}-3-methylazetidin-3-yl)carbamate 945-[2-(3-amino-3-methylazetidin-1-yl)-2-oxoethyl]-3-(3,4- 3.1dichlorophenyl)-4H,5H-thieno[3,2-c]pyridin-4-one 4018-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[2-(3-fluoro-3- 160methylazetidin-1-yl)-2-oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 74tert-butyl N-(1-{2-[3-(3-chloro-4-fluorophenyl)-4-oxo-4H,5H- 4.7thieno[3,2-c]pyridin-5-yl]acetyl}-3-methylazetidin-3-yl)carbamate 955-[2-(3-amino-3-methylazetidin-1-yl)-2-oxoethyl]-3-(3-chloro-4- 1fluorophenyl)-4H,5H-thieno[3,2-c]pyridin-4-one 753-(5,6-dichloropyridin-3-yl)-5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 78oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 763-(5,6-dichloropyridin-3-yl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 77oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 77 tert-butylN-[1-(2-{3-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo- −6.44H,5H-thieno[3,2-c]pyridin-5-yl}acetyl)-3-methylazetidin-3- yl]carbamate96 5-[2-(3-amino-3-methylazetidin-1-yl)-2-oxoethyl]-3-[4-fluoro-3- 4 3(trifluoromethyl)phenyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2703-(3,4-dichlorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 130oxoethyl]-1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2363-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoro-3- 140methylazetidin-1-yl)-2-oxoethyl]-1-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 785-(2-{5-azaspiro[2.3]hexan-5-yl}-2-oxoethyl)-3-(3,4-dichlorophenyl)- 534H,5H-thieno[3,2-c]pyridin-4-one 79 tert-butyl6-{2-[3-(3-chloro-4-fluorophenyl)-4-oxo-4H,5H-thieno[3,2- 18c]pyridin-5-yl]acetyl}-1,6-diazaspiro[3.3]heptane-1-carboxylate 2713-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 140oxoethyl]-1-(1-methyl-1H-1,2,3-triazol-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2853-(3-chloro-4-fluorophenyl)-1-cyclopropyl-5-[2-(3-fluoro-3- 140methylazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one80 5-(2-{5-azaspiro[2.3]hexan-5-yl}-2-oxoethyl)-3-[4-fluoro-3- 64(trifluoromethyl)phenyl]-4H,5H-thieno[3,2-c]pyridin-4-one 2863-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 130oxoethyl]-1-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2803-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 73oxoethyl]-1-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one281 3-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2-150 oxoethyl]-1-(2-fluoroethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 183-(4-chloro-3-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 120oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 193-(5-chloro-6-fluoropyridin-3-yl)-5-[2-(3-fluoro-3-methylazetidin-1- 35yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 973-(3-chloro-4-fluorophenyl)-5-(2-{1,6-diazaspiro [3.3]heptan-6-yl}-2-2.8 oxoethyl)-4H,5H-thieno[3,2-c]pyridin-4-one 203-(3,4-difluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 41oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 213-[4-chloro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoro-3- 120methylazetidin-1-yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 4261-(3-chloro-4-fluorophenyl)-7-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 30oxoethyl]-3-methyl-7H,8H-imidazo[1,5-a]pyrazin-8-one 4301-(3-chloro-4-fluorophenyl)-7-[2-(3,3-difluoroazetidin-1-yl)-2- 7.3oxoethyl]-3-methyl-7H,8H-imidazo[1,5-a]pyrazin-8-one 4168-(3-chloro-4-fluorophenyl)-2-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 110oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4178-(3-chloro-4-fluorophenyl)-2-[2-(3,3-difluoroazetidin-1-yl)-2- 20oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 3283-(3-chloro-4-fluorophenyl)-5-[2-(3,3-difluoroazetidin-1-yl)-2- 29oxoethyl]-4H,5H-pyrazolo[1,5-a]pyrazin-4-one 223-(4-chloro-3-methylphenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 130oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 235-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-3-(4-fluoro-3- 100methylphenyl)-4H,5H-thieno[3,2-c]pyridin-4-one 3293-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 110oxoethyl]-4H,5H-pyrazolo[1,5-a]pyrazin-4-one 813-(3-chloro-4-fluorophenyl)-5-{2-[3-fluoro-3-(fluoromethyl)azetidin- 1401-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 2373-(3-chloro-4-fluorophenyl)-1-cyclopropyl-5-[2-(3-ethyl-3- 79fluoroazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one445 1-(3-chloro-4-fluorophenyl)-7-[2-(3-fluoro-3-methylazetidin-1-yl)-2-34 oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 4461-[4-fluoro-3-(trifluoromethyl)phenyl]-7-[2-(3-fluoro-3- 68methylazetidin-1-yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 4471-(3,4-dichlorophenyl)-7-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 58oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 823-(3,4-dichlorophenyl)-5-{2-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]-140 2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 835-{2-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-3-[4-fluoro-140 3-(trifluoromethyl)phenyl]-4H,5H-thieno[3,2-c]pyridin-4-one 4028-(3-chloro-4-fluorophenyl)-2-{2-[3-fluoro-3-(fluoromethyl)azetidin- 1301-yl]-2-oxoethyl}-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4353-cyclopropyl-1-(3,4-dichlorophenyl)-7-[2-(3-fluoro-3-methylazetidin-120 1-yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 4038-(3,4-dichlorophenyl)-2-{2-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]-130 2-oxoethyl}-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4188-(3-chloro-4-fluorophenyl)-2-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 74oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4048-(5,6-dichloropyridin-3-yl)-2-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 58oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4361-(3-chloro-4-fluorophenyl)-3-cyclopropyl-7-[2-(3-fluoro-3- 100methylazetidin-1-yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 4373-cyclopropyl-1-(5,6-dichloropyridin-3-yl)-7-[2-(3-fluoro-3- 65methylazetidin-1-yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 4383-cyclopropyl-1-[4-fluoro-3-(trifluoromethyl)phenyl]-7-[2-(3-fluoro-3-79 methylazetidin-1-yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one431 1-(3-chloro-4-fluorophenyl)-7-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2-−3.9 oxoethyl]-3-methyl-7H,8H-imidazo[1,5-a]pyrazin-8-one 4058-(5,6-dichloropyridin-3-yl)-2-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 61oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4068-(5,6-dichloropyridin-3-yl)-2-{2-[3-fluoro-3-(fluoromethyl)azetidin- 851-yl]-2-oxoethyl}-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 2871-cyclopropyl-3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-[2-(3-fluoro-3-140 methylazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2881-cyclopropyl-3-(3,4-dichlorophenyl)-5-[2-(3-fluoro-3-methylazetidin-130 1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 4198-(3,4-dichlorophenyl)-2-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 110oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4245-(3-chloro-4-fluorophenyl)-3-[2-(3-fluoro-3-methylazetidin-1-yl)-2-0.55 oxoethyl]-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one 4072-{2-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-8-[4-fluoro-130 3-(trifluoromethyl)phenyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 2891-cyclopropyl-3-(5,6-dichloropyridin-3-yl)-5-[2-(3-fluoro-3- 120methylazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one2901-cyclopropyl-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-3-(4-120 fluoro-3-methylphenyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2913-(5-chloro-6-fluoropyridin-3-yl)-1-cyclopropyl-5-[2-(3-fluoro-3- 80methylazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one292 3-(4-chloro-3-methylphenyl)-1-cyclopropyl-5-[2-(3-fluoro-3- 140methylazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one439 1-(3-chloro-4-fluorophenyl)-3-cyclopropyl-7-{2-[3-fluoro-3- 120(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-7H,8H-imidazo[1,5-a]pyrazin-8-one 4403-cyclopropyl-1-(3,4-dichlorophenyl)-7-{2-[3-fluoro-3- 110(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-7H,8H-imidazo[1,5-a]pyrazin-8-one 4411-(5-chloro-6-fluoropyridin-3-yl)-3-cyclopropyl-7-[2-(3-fluoro-3- 46methylazetidin-1-yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 4423-cyclopropyl-7-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-1-(4- 65fluoro-3-methylphenyl)-7H,8H-imidazo[1,5-a]pyrazin-8-one 4431-(4-chloro-3-methylphenyl)-3-cyclopropyl-7-[2-(3-fluoro-3- 120methylazetidin-1-yl)-2-oxoethyl]-7H,8H-imidazo[1,5-a]pyrazin-8-one 2931-cyclopropyl-3-(3,4-dichlorophenyl)-5-{2-[3-fluoro-3- 160(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 4255-(3,4-dichlorophenyl)-3-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 27oxoethyl]-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one 2823-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 120oxoethyl]-1-(oxetan-3-yl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 2543-(3-chloro-4-fluorophenyl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 140oxoethyl]-1-(methoxymethyl)-1H,4H,5H-pyrrolo[3,2-c]pyridin-4-one 843-(6-chloro-5-methylpyridin-3-yl)-5-[2-(3-fluoro-3-methylazetidin-1- 39yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 853-(6-chloro-5-methylpyridin-3-yl)-5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-16 2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 863-(6-chloro-5-methylpyridin-3-yl)-5-{2-[3-fluoro-3- 17(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 875-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-3-(6-fluoro-5- −4.2methylpyridin-3-yl)-4H,5H-thieno[3,2-c]pyridin-4-one 885-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(6-fluoro-5- 20methylpyridin-3-yl)-4H,5H-thieno[3,2-c]pyridin-4-one 895-{2-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-3-(6-fluoro-16 5-methylpyridin-3-yl)-4H,5H-thieno[3,2-c]pyridin-4-one 4088-(6-chloro-5-methylpyridin-3-yl)-2-[2-(3-fluoro-3-methylazetidin-1- 51yl)-2-oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4098-(6-chloro-5-methylpyridin-3-yl)-2-{2-[3-fluoro-3- 33(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4108-(6-chloro-5-methylpyridin-3-yl)-2-[2-(3-ethyl-3-fluoroazetidin-1-yl)-34 2-oxoethyl]-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 2941-cyclopropyl-3-(5,6-dichloropyridin-3-yl)-5-[2-(3-ethyl-3- 88fluoroazetidin-1-yl)-2-oxoethyl]-1H,4H,5H-pyrrolo[3,2-c]pyridin-4- one90 3-(5-chloro-6-methylpyridin-3-yl)-5-[2-(3-fluoro-3-methylazetidin-1-75 yl)-2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 913-(5-chloro-6-methylpyridin-3-yl)-5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-74 2-oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 923-(5-chloro-6-methylpyridin-3-yl)-5-{2-[3-fluoro-3- 70(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 1363-chloro-5-{5-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-4-oxo- 174H,5H-thieno[3,2-c]pyridin-3-yl}pyridine-2-carbonitrile 1373-chloro-5-{5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-4-oxo- 224H,5H-thieno[3,2-c]pyridin-3-yl}pyridine-2-carbonitrile 1383-chloro-5-(5-{2-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]-2- 10oxoethyl}-4-oxo-4H,5H-thieno[3,2-c]pyridin-3-yl)pyridine-2- carbonitrile4208-(5,6-dichloropyridin-3-yl)-2-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 69oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4218-(5,6-dichloropyridin-3-yl)-2-{2-[3-fluoro-3-(fluoromethyl)azetidin- 921-yl]-2-oxoethyl}-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 4228-(5,6-dichloropyridin-3-yl)-2-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 29oxoethyl]-4-methyl-1H,2H-pyrrolo[1,2-a]pyrazin-1-one 1393-(5,6-difluoropyridin-3-yl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 11oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1403-(2-chloropyrimidin-5-yl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 3.1oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1413-(2-chloropyrimidin-5-yl)-5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- −4.1oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1423-(2-chloropyrimidin-5-yl)-5-{2-[3-fluoro-3-(fluoromethyl)azetidin-1-−4.2 yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 1433-(5,6-difluoropyridin-3-yl)-5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 15oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1443-(5,6-difluoropyridin-3-yl)-5-{2-[3-fluoro-3-(fluoromethyl)azetidin-9.8 1-yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 1453-(6-chloropyrazin-2-yl)-5-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 3oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one 1463-(6-chloropyrazin-2-yl)-5-{2-[3-fluoro-3-(fluoromethyl)azetidin-1- −3.8yl]-2-oxoethyl}-4H,5H-thieno[3,2-c]pyridin-4-one 1473-(6-chloropyrazin-2-yl)-5-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- −0.39oxoethyl]-4H,5H-thieno[3,2-c]pyridin-4-one

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted below, are hereby incorporated by reference in their entirety forall purposes as if each individual publication or patent wasspecifically and individually incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The full scope of the inventionshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention.

What is claimed is:
 1. A method for treating a neuropsychiatric disorderselected from schizophrenia, depression, an autism spectrum disorder,and Rett syndrome in a subject comprising administering to said subjecta therapeutically effective amount of a compound represented by FormulaI

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:rings A and B are a fused [5,6] or [6,6] heteroaromatic system; Q is Nor CR⁶; T is N or CR⁶; and y is 0 or 1 wherein when y is 1, U¹ and U²are C; W and V are each independently selected from CR⁶; one of Y and Xis CR³ and one of Y and X is CR⁶; and when y is 0: X is CR³ or NR³³; Wis selected from the group consisting of CR⁶, N or S; V is selected fromthe group consisting of N, NR⁷, CR⁶, S and O; U¹ and U² may each be C orN; wherein when one of U¹ and U² is N the other is C; and when Q is CR⁶,T is N, W is CR⁶ and X is CR³; V is not S; L¹ is a bond or C₁₋₄ alkyleneoptionally interrupted by O, and optionally substituted on a carbon notbound to the ring nitrogen with one, two, or three substituents eachindependently selected from the group consisting of halogen, OH, cyanoand —NR^(a)R^(b); R¹ and R², together with the nitrogen to which theyare attached, form a 4-6 membered monocyclic heterocyclic ringoptionally substituted on a carbon by one, two or more substituents eachselected from the group consisting of halogen, cyano, oxo, hydroxyl andC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted by one,two or three halogens; R³ is phenyl, thiophenyl, pyrimidinyl, pyrazinylor pyridinyl, each optionally substituted by one or two substituentseach independently selected from the group consisting of halogen andC₁₋₃alkyl, wherein said C₁₋₃ alkyl is optionally substituted by one, twoor three halogens; R³³ is selected from the group consisting of phenyl,naphthyl, heteroaryl, heterocyclyl and C₃₋₆ cycloalkyl, wherein R³³ isoptionally substituted with one, two or three substituents eachindependently selected from the group consisting of C₁₋₄ alkyl, halogen,hydroxyl, C₁₋₄ alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₁₋₆alkyl-S(O)₂—, C₁₋₆ alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b),C(O)OH, C₁₋₄ alkoxycarbonyl, and NR^(a)R^(b)carbonyl; wherein C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆ alkyl-S(O)₂— and C₁₋₆alkylcarbonyl may be optionally substituted by one or more substituentseach selected from the group consisting of halogen, hydroxyl, cyano, andNR^(a)R^(b); R⁶ is independently selected for each occurrence from thegroup consisting of hydrogen, halogen, cyano, C₁₋₄ alkyl, C(O)OH, C(O)H,—C(═NH)—NR^(a)R^(c), phenyl, pyridinyl and pyrimidinyl, wherein saidC₁₋₄ alkyl for R⁶ is optionally substituted by one or two substituentseach selected from the group consisting of —NR^(a)R^(b), C₁₋₄alkoxy,halogen, cyano, hydroxyl, C(O)H, and ═NR^(a), and wherein said phenylfor R⁶ is optionally substituted by one or two substituents eachselected from the group consisting of NR^(a)R^(b), C₁₋₄ alkoxy, halogen,cyano, hydroxyl, C(O)H, and ═NR^(a); R⁷ is selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,heterocyclyl, heteroaryl, and phenyl; wherein C₁₋₆ alkyl, C₂₋₆ alkenyland C₃₋₆ cycloalkyl may optionally be substituted by one or moresubstituents each selected from the group consisting of halogen,hydroxyl, C₁₋₄ alkoxy (optionally substituted by halogen or—Si(R_(s))₀₋₃ (wherein R_(s) is H or C₁₋₆alkyl)), cyano, —Si(R_(s))₀₋₃(wherein R_(s) is H or C₁₋₆ alkyl), —O—Si(R_(s))₀₋₃ (wherein R_(s) is Hor C₁₋₆ alkyl), and NR^(a)R^(b); R^(c) is selected from the groupconsisting of hydrogen, C₁₋₃alkyl, and hydroxyl; and R^(a) and R^(b) areindependently selected, for each occurrence, from the group consistingof hydrogen, C₁₋₄ alkylcarbonyl, —C(O)—O—C₁₋₄alkyl, C₃₋₆ cycloalkyl andC₁₋₃alkyl; wherein C₁₋₃alkyl and C₃₋₆ cycloalkyl may optionally besubstituted on a carbon not bound to the nitrogen by one or moresubstituents each selected from the group consisting of fluorine, cyano,oxo and hydroxyl; or R^(a) and R^(b), together with the nitrogen towhich they are attached, form a 4-6 membered heterocyclic ring which mayhave an additional heteroatom selected from O, S, or N; and wherein the4-6 membered heterocyclic ring may optionally be substituted on a carbonnot bound to the nitrogen by one or more substituents selected from thegroup consisting of fluorine, methyl, cyano, oxo and hydroxyl.
 2. Themethod of claim 1, wherein the fused [5,6] or [6,6] heteroaromaticsystem is selected from the group consisting of:


3. The method of claim 1, wherein the rings A and B are a fused [5,6]heteroaromatic system.
 4. The method of claim 1, wherein the rings A andB are a fused [5,6] heteroaromatic system selected from the groupconsisting of:


5. The method of claim 1, wherein the rings A and B represent thefollowing fused [5,6] heteroaromatic system:


6. The method of claim 1, wherein L¹ is —CH₂—.
 7. The method of claim 1,wherein R³ is phenyl, optionally substituted by one or two substituentseach independently selected from the group consisting of Cl, F, Br, andCF₃.
 8. The method of claim 1, wherein the compound is represented by:

wherein U¹ and U² may each be C or N; wherein when one of U¹ and U² is Nthe other is C; T is N or CR⁶; R⁶⁶ and R⁶⁷ are each independentlyselected from the group consisting of halogen and C₁₋₄ alkyl, whereinsaid C₁₋₄ alkyl is optionally substituted by one, two, threesubstituents selected from halogen, hydroxyl, cyano and NR^(a)R^(b); andV is selected from the group consisting of N, NR⁷, CR⁶⁶ and S.
 9. Themethod of claim 8, wherein U¹ is N and U² is C.
 10. The method of claim1, wherein V is NR⁷.
 11. The method of claim 1, wherein U¹ is C and U²is N.
 12. The method of claim 1, wherein V is N.
 13. The method of claim8, wherein the compound is represented by:

wherein V is NR⁷ or S.
 14. The method of claim 13, wherein R⁷ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, pyridyl, andphenyl; wherein C₁₋₆ alkyl is optionally substituted by one or moresubstituents each selected from the group consisting of halogen,hydroxyl, and C₁₋₄alkoxy.
 15. A method of treating cognitive impairmentassociated with schizophrenia or Phelan-McDermid Syndrome comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound represented by Formula I

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:rings A and B are a fused [5,6] or [6,6] heteroaromatic system; Q is Nor CR⁶; T is N or CR⁶; and y is 0 or 1 wherein when y is 1, U¹ and U²are C; W and V are each independently selected from CR⁶; one of Y and Xis CR³ and one of Y and X is CR⁶; and when y is 0: X is CR³ or NR³³; Wis selected from the group consisting of CR⁶, N or S; V is selected fromthe group consisting of N, NR⁷, CR⁶, S and O; U¹ and U² may each be C orN; wherein when one of U¹ and U² is N the other is C; and when Q is CR⁶,T is N, W is CR⁶ and X is CR³; V is not S; L¹ is a bond or C₁₋₄ alkyleneoptionally interrupted by O, and optionally substituted on a carbon notbound to the ring nitrogen with one, two, or three substituents eachindependently selected from the group consisting of halogen, OH, cyanoand —NR^(a)R^(b); R¹ and R², together with the nitrogen to which theyare attached, form a 4-6 membered monocyclic heterocyclic ringoptionally substituted on a carbon by one, two or more substituents eachselected from the group consisting of halogen, cyano, oxo, hydroxyl andC₁₋₆ alkyl, wherein said C₁₋₆alkyl is optionally substituted by one, twoor three halogens; R³ is phenyl, thiophenyl, pyrimidinyl, pyrazinyl orpyridinyl, each optionally substituted by one or two substituents eachindependently selected from the group consisting of halogen andC₁₋₃alkyl, wherein said C₁₋₃ alkyl is optionally substituted by one, twoor three halogens; R³³ is selected from the group consisting of phenyl,naphthyl, heteroaryl, heterocyclyl and C₃₋₆ cycloalkyl, wherein R³³ isoptionally substituted with one, two or three substituents eachindependently selected from the group consisting of C₁₋₄ alkyl, halogen,hydroxyl, C₁₋₄ alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₁₋₆alkyl-S(O)₂—, C₁₋₆ alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b),C(O)OH, C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; wherein C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂— and C₁₋₆alkylcarbonyl may be optionally substituted by one or more substituentseach selected from the group consisting of halogen, hydroxyl, cyano, andNR^(a)R^(b); R⁶ is independently selected for each occurrence from thegroup consisting of hydrogen, halogen, cyano, C₁₋₄ alkyl, C(O)OH, C(O)H,—C(═NH)—NR^(a)R^(c), phenyl, pyridinyl and pyrimidinyl, wherein saidC₁₋₄ alkyl for R⁶ is optionally substituted by one or two substituentseach selected from the group consisting of —NR^(a)R^(b), C₁₋₄alkoxy,halogen, cyano, hydroxyl, C(O)H, and ═NR^(a), and wherein said phenylfor R⁶ is optionally substituted by one or two substituents eachselected from the group consisting of NR^(a)R^(b), C₁₋₄ alkoxy, halogen,cyano, hydroxyl, C(O)H, and ═NR^(a); R⁷ is selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,heterocyclyl, heteroaryl, and phenyl; wherein C₁₋₆ alkyl, C₂₋₆ alkenyland C₃₋₆ cycloalkyl may optionally be substituted by one or moresubstituents each selected from the group consisting of halogen,hydroxyl, C₁₋₄ alkoxy (optionally substituted by halogen or—Si(R_(s))₀₋₃ (wherein R_(s) is H or C₁₋₆alkyl)), cyano, —Si(R_(s))₀₋₃(wherein R_(s) is H or C₁₋₆ alkyl), —O—Si(R_(s))₀₋₃ (wherein R_(s) is Hor C₁₋₆ alkyl), and NR^(a)R^(b); R^(c) is selected from the groupconsisting of hydrogen, C₁₋₃alkyl, and hydroxyl; and R^(a) and R^(b) areindependently selected, for each occurrence, from the group consistingof hydrogen, C₁₋₄ alkylcarbonyl, —C(O)—O—C₁₋₄ alkyl, C₃₋₆ cycloalkyl andC₁₋₃ alkyl; wherein C₁₋₃ alkyl and C₃₋₆ cycloalkyl may optionally besubstituted on a carbon not bound to the nitrogen by one or moresubstituents each selected from the group consisting of fluorine, cyano,oxo and hydroxyl; or R^(a) and R^(b), together with the nitrogen towhich they are attached, form a 4-6 membered heterocyclic ring which mayhave an additional heteroatom selected from O, S, or N; and wherein the4-6 membered heterocyclic ring may optionally be substituted on a carbonnot bound to the nitrogen by one or more substituents selected from thegroup consisting of fluorine, methyl, cyano, oxo and hydroxyl.
 16. Themethod of claim 15, wherein the fused [5,6] or [6,6] heteroaromaticsystem is selected from the group consisting of:


17. The method of claim 15, wherein the rings A and B are a fused [5,6]heteroaromatic system.
 18. The method of claim 15, wherein the rings Aand B are a fused [5,6] heteroaromatic system selected from the groupconsisting of:


19. The method of claim 15, wherein the rings A and B represent thefollowing fused [5,6] heteroaromatic system:


20. The method of claim 15, wherein L¹ is —CH₂—.
 21. The method of claim15, wherein R³ is phenyl, optionally substituted by one or twosubstituents each independently selected from the group consisting ofCl, F, Br, and CF₃.
 22. The method of claim 15, wherein the compound isrepresented by:

wherein U¹ and U² may each be C or N; wherein when one of U¹ and U² is Nthe other is C; T is N or CR⁶; R⁶⁶ and R⁶⁷ are each independentlyselected from the group consisting of halogen and C₁₋₄ alkyl, whereinsaid C₁₋₄ alkyl is optionally substituted by one, two, threesubstituents selected from halogen, hydroxyl, cyano and NR^(a)R^(b); andV is selected from the group consisting of N, NR⁷, CR⁶⁶ and S.
 23. Themethod of claim 22, wherein U¹ is N and U² is C.
 24. The method of claim15, wherein V is NR⁷.
 25. The method of claim 15, wherein U¹ is C and U²is N.
 26. The method of claim 15, wherein V is N.
 27. The method ofclaim 22, wherein the compound is represented by:

wherein V is NR⁷ or S.
 28. The method of claim 27, wherein R⁷ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, pyridyl, andphenyl; wherein C₁₋₆ alkyl is optionally substituted by one or moresubstituents each selected from the group consisting of halogen,hydroxyl, and C₁₋₄alkoxy.